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WELCOME TO 2022 LONG-ACTING INJECTABLES CONFERENCE

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René Holm

University of Southern Denmark

Bio:

Dr. René Holm is a Professor of Faculty in pharmaceutical physical chemistry at the University of Southern Denmark. After receiving Master and PhD degree in pharmaceutics from the University of Copenhagen, Denmark, in 2002, he started his carrier in the pharmaceutical industry at H.Lundbeck in 2001 and changed to Janssen in 2016. Dr. Holm has worked within pharmaceutical development, formulations for non-clinical testing in drug discovery, physical chemistry and material science covering both small and large molecules. In 2021 Dr. Holm engaged into a carrier change and became a full professor at the University of Southern Denmark.

Dr. Holm is (co-) author of more than 220 original articles in peer-reviewed journals and patents in the field of biopharmaceutics, preformulation, formulation and physical pharmacy and book chapters and is co-inventor on 12 published patents. He further an honorary professor in physical chemistry at the Department of Science and Environment, University of Roskilde, Denmark.

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Abstract:

Long-acting injectables (LAIs) provide a slow, sustained release of the active pharmaceutical ingredient after administration. LAI formulations can help ensuring effective drug usage, reduced frequency of administration, and enhanced therapy adherence. LAIs have attracted special interest in therapeutic areas such as schizophrenia, HIV, and tuberculosis, where repeated drug administration is required.

Most marketed LAI formulations are aqueous suspensions, where polymers and surfactants are added to the formulation to control the physical stability.

This talk will provide an introduction to LAI’s with focus on the formulation parameters of importance for the physical stability as well as the biopharmaceutical performance.

Noor Al-Rifai

The Janssen Pharmaceutical
Companies of Johnson & Johnson

Bio:

Noor Al-Rifai is a Senior Scientist at The Janssen Pharmaceutical Companies of J&J. In this role, Noor is delivering on engineering strategies for drug products to optimize development work and tech transfers. Noor has particular subject matter expertise in long acting injectables, from development of process control strategies to mechanistic models for process optimisation and scale-up. Noor is a chartered Chemical Engineer, has a PhD in Chemical Engineering from UCL and prior experience in solids and liquids formulation at Merck Sharp & Dohme and Procter & Gamble.​

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Abstract:

Long acting injectables (LAI) therapy is gaining increasing interest as it has the potential to improve patient adherence, efficacy and/or tolerability. The predominant manufacturing method for suspension-based LAIs is top-down comminution in a sterile environment; this presentation will demonstrate challenges associated with process design, scale-up, and options towards control strategies.

Mariana Hugo Silva

The Janssen Pharmaceutical
Companies of Johnson & Johnson

Bio:

Mariana has an Integrated Master’s degree in Biomedical Engineering from the University of Coimbra. During this period, she worked on a collaborative project between the University of Coimbra and the Pharmacy Faculty of Santiago de Compostela, which culminated in the development of innovative biopolymer-based scaffolds combining silica-based nanomaterials with safe ionic liquids having potential features for a wide range of engineering and biotechnology application. After obtaining her master’s degree, she continued working as a researcher on different fields and learn new methods in three research institutes (CFisUC, CNC, Karolinska Institutet) both in Portugal and in Sweden.

 

Mariana is currently pursuing her PhD in an Industrial Training Network – LongActNow which is a Marie SkÅ‚odowska-Curie funded program to study bottom-up approaches to produce the next generation of LAIs. She's conducting her research between academia (University of Limerick, Trinity College Dublin) and industry (Janssen Pharmaceutica, Beerse, Belgium).

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Abstract:

Long-acting injectables (LAIs) are a formulation strategy that provide a slow, sustained release of the drug. Among the different techniques to produce drug particles, liquid antisolvent (LAS) precipitation is fast, easy and cost-efficient. This work investigated the technical feasibility of generating LAIs using a novel continuous LAS approach.

Microparticles of indomethacin were successfully prepared and stabilized with excipients, and the stable polymorphic form was achieved by this continuous route. The particle size distribution and surface properties of the particles were similar to those produced via corresponding laboratory-scale batch mode process, indicating that product quality was retained during continuous processing.

This energy efficient bottom-up method to produce drug suspensions with a reduced risk of contamination and fewer processing steps may prove to be comparable to industrially accepted top-down approaches. Furthermore, it has the potential to be applied to a variety of drugs to produce LAI suspensions with a target PSD and a stable polymorphic form.

Fidel Mendéz Canellas

University of Limerick

Bio:

Fidel completed his undergraduate degree in Nanoscience and Nanotechnology at the Universitat Autònoma de Barcelona in 2018. He then completed his master degree in Nanomedicine at Swansea University in 2019. He is now working in his industrial PhD (Marie SkÅ‚odowska-Curie actions) titled “Nucleation, Crystallization And Formulation Of Injectable Suspensions With Long-Acting Activity”. He is working in the SSPC (Science Foundation Ireland Research Centre for Pharmaceuticals) at the University of Limerick and Janssen Pharmaceuticals (Belgium). The goal of his project is to produce an injectable suspension of an active pharmaceutical ingredient (API) which can continue to release the API for a specific time.​

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Abstract:

Top-down methods are widely used in industry for the micronisation of particles and production of suspensions. The reduction of particle size is a strategy for the formulation of poorly soluble active pharmaceutical ingredients (APIs). Top-down methods can be classified as wet and dry top-down methods depending on the media used for milling the particles and thus, different techniques may affect the particle suspension characteristics. In this work, two methods; jet milling (dry top-down) and microfluidization (wet top-down), and two APIs; indomethacin and naproxen, were selected to constitute suspensions. The same excipient combinations, concentration and particle size were targeted with both top-down techniques, and the particle size stability, solid state and, morphology were compared.

Jerry Heng

Imperial College London

Bio:

Jerry Heng is currently a Professor in Particle Technology and Director of UG Studies at the Department of Chemical Engineering at Imperial College London. He obtained his PhD in Chemical Engineering from Imperial College London (2006) and a B.Eng in Chemical Engineering from Universiti Teknologi Malaysia (2002). His research group aims to understand the role of surfaces and interfaces in nucleation and crystal growth with the aim of developing crystallisation as a separation strategy for the purification of biopharmaceuticals. Jerry is currently an EPSRC Manufacturing the Future Fellow, a Fellow of the Royal Society of Chemistry and Editor-in-Chief of the IChemE's journal - Chemical Engineering Research and Design.

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Abstract:

The purification of high molecular weight proteins and peptides, for their use in biopharmaceutical drug therapeutics, can still account for a significant proportion of the drug development cost. However, advances in the optimisation of crystallisation conditions have seen significant increase in the scalability of protein crystallisation. This has seen crystallisation emerge as a more economic and greener alternative to the existing chromatographic methods typically utilised in peptide and protein purification. Mechanistic process modelling, based on population balance equations to represent the underpinning physical phenomena, has proved a computationally efficient method of predicting optimal crystallisation conditions of the purification of small molecule active pharmaceutical ingredients. However, this has yet to be expanded into the crystallisation of biopharmaceutical proteins. This talk will focus on my group’s efforts to control nucleation and crystallisation of complex macromolecules (proteins and homo-peptides); using 3D-nanotemplates for a range of model proteins (eg thaumatin, con A, catalase, etc) and the use of soft templates (eg amino acids) for insulin. For peptides, the effects of chain length and thermodynamic properties (eg solubility) is determined to establish a rational design of the crystallisation conditions using glycine homopeptides as a model. Selective crystallisation as a purification step is demonstrated on model protein mixtures (lysozyme-thaumatin and lysozyme-albumin), the influence of impurities and the purification of a therapeutic monoclonal antibody (Anti-CD20). Finally, the talk will also report on scaling up efforts from small scale batch crystallisers to continuous crystallisation platforms, utilising gProms as a process modelling tool for optimising protein crystallisation. This talk will provide some insights into the challenges and opportunities in crystallisation as a purification unit process for proteins and peptides.

Amábille Kloc

TU Dortmund

Bio:

Graduated in Chemical Engineering (2017) at Federal Univesity of Technology - Paraná, Brazil. Completed Master's degree in Chemical Engineering (2020) at Federal University of Paraná - Brazil, with a thesis entitled "Phase Equilibrium of {carbon dioxide + levulinic acid + organic solvents} systems". Currently an Industrial PhD candidate at the Bio- and Chemical Engineering Department at Technische Universität Dortmund - Germany, with a project granted by the EU Program Marie Sklodowska-Curie Actions. The project is entitled "Solubility of Crystalline APIs and Stability of Crystal Suspension". The general objective of this project is to investigate the thermodynamic equilibrium between pharmaceutical compounds and different solvents from both experimental and theoretical point of view, by applying the thermodynamic model PC-SAFT.

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Abstract:

Poor water-soluble drugs show low bioavailability, jeopardizing the active pharmaceutical ingredient (API) release in the body. Reducing the API particle size to the nanoscale range is a method to overcome the low bioavailability of poor water-soluble APIs.  By decreasing the particle size and, thus, increasing the surface area, the dissolution rate in the medium is enhanced. Besides the faster dissolution rate, nanoparticles also offer the possibility of high drug loading.

This talk will focus on the investigation of the influence of particle size on API solubility, from a modelling perspective. The API melting point depression caused by particle size reduction was calculated as a function of particle radius, molar volume, and surface tension. Furthermore, PC-SAFT Equation of State was used to predict the solubility of nano-sized APIs in water.

Fatima Anjum

TU Dortmund

Bio:

Fatima obtained her bachelor’s degree in chemical engineering from University of Engineering and Technology, Lahore in 2017. She then worked as Graduate trainee engineer at Bulleh Shah Packaging Limited where she worked primarily at effluent treatment. This induced an interest of membrane technology in her and she came to Europe in 2018 to pursue Erasmus Mundus Masters in Membrane Engineering. Currently, she is an EU industrial doctorate researcher (Marie SkÅ‚odowska-Curie action) at Technical University Dortmund. As part of her doctorate program, she has also been carrying out research at Janssen Pharmaceuticals, Beerse. The objective of her work is to develop continuous bottom-up production process of long-acting injectables. She has been working on membrane-based process to remove residual organic solvent as well as optimize excipients’ (stabilizers) usage in crystalline API suspensions generated via solvent/anti-solvent crystallization process.

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Abstract:

Long-acting crystal suspensions of active pharmaceutical ingredients (API) have recently gained popularity over common dosing strategies owing to the benefits such as sustained release, better intermuscular penetration, and improved patients’ convenience. These suspensions can be generated by top-down methods (breaking down large crystals) or by bottom-up methods (building up crystals from molecules). In either methods, polymers and surfactants are used as excipients to stabilize the crystals in terms of particle size and physical form. This talk will highlight the role of excipients at different steps throughout the production process of Long acting crystal suspensions. Within this work, the excipients’ requirement has been investigated during the crystal’s formation. Following, a membrane-based separation process was used to purify crystal suspension by removing residual solvent as per ICH guidelines. Moreover, the membrane process was employed as an analytical tool to study the interactions of crystals and excipient as well as influence of excipients’ concentration on the stability of crystals in the suspension. This work de-coupled the excipients’ requirement during and post crystal formation and has provided useful insights into how different excipient interacts with different API crystals systems.

Snehashis Nandi

The Janssen Pharmaceutical
Companies of Johnson & Johnson

Bio:

Snehashis obtained his bachelors degree in Pharmacy from Jadavpur University, Kolkata in 2016. Being Pharmacist by education, he then completed his master’s degree in Pharmaceutics at NIPER, Mohali in 2018. He then work as formulation scientist at Dr. Reddy’s Lab, Hyderabad and Bristol Myers Squibb, Bangalore. Currently, He is an EU industrial doctoral researcher (Marie SkÅ‚odowska-Curie actions fellow), working as a scientist in Janssen Pharmaceutica (Belgium) and also in the SSPC (Science Foundation Ireland Research Centre for Pharmaceuticals) at the University of Limerick. The goal of his project is to develop an integrated bottom-up process as potential alternative for manufacturing long-acting injectable suspensions at the industrial scale and validate toolboxes for novel complex APIs..​

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Abstract:

Suspension based formulation is the most preferred delivery system for the long-acting injectables (LAIs). In this work, we investigated the operational feasibility of generation, and stabilization of micro/nano sized long-acting injectable suspension by an integrated bottom-up approach using a practically insoluble model drug, itraconazole (ITZ). Based on initial screening, a novel automatic microchannel mixer assisted liquid antisolvent crystallization set up was assembled and operating parameters were optimized for continuous production of a homogeneous stable suspension. Our work revealed that the interplay between thermodynamic driving force, crystallization kinetics, mixing hydrodynamics is critical for the process design and optimization. These critical attributes offered the flexibility of adjusting the process to produce either nano or microsuspension as per the biopharmaceutical need. Then, a membraned based solvent switch process was integrated to remove residual solvent below parenterally approved limit. Thereafter, the challenge of concentrating up in the downstream process was solved by centrifugal filtration and followed by resuspension to LAI concentration range (300 mg/mL). The long-term stability of the final suspension was monitored against the suspension of each 3 stages at 25°C for particle size, solid state and resuspendability over time up to 1.5 years. Our work set up a complete framework for the bottom-up manufacturing LAI suspensions formulation at the industrial scale.

Cherise Scott

Unitaid

Bio:

Dr Cherise Scott (Technical Manager, Strategy team – Unitaid) is a global health specialist with over a decade of experience in developing and advancing innovations and products for neglected diseases. Dr. Scott’s career spans preclinical to market introduction for medicines and vaccines. Her current work encompasses identifying and supporting interventions to overcome access barriers to innovative treatment, diagnosis, and prevention tools for major diseases in low- and middle-income countries with a particular focus on the areas of tuberculosis, HCV, long-acting technologies, innovative delivery forms for paediatric treatment, regulatory and intellectual property.​

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Abstract:

​The objective of this session is to introduce participants to the challenges hindering success in management of key diseases in lower- and middle-income countries (L/MICs) and the role of long-acting technologies in the Global Health responses. There is a need to think early about access and consider how to shape a market that addresses global health needs and avoid the gap that would leave a considerable proportion of humanity left out of these advances. Ongoing work and potential impact in this area will be highlighted including projects being funded by Unitaid.  Specific topics to be covered include: 1) interest of the global health community to accelerate the availability and introduction of long-acting products fit-for-purpose for L/MICs 2) funding channels for L/MICs-customized products 3) shaping target product profiles to include specific conditions for resource-limited settings and 4) challenges related to regulatory, quality, intellectual property, affordability, and future access.

Mario Hellings

The Janssen Pharmaceutical
Companies of Johnson & Johnson

Bio:

Mario Hellings received his doctor’s degree in Science in 2004 and subsequently started working for Janssen. Since 2015, Mario is working as a Scientific Director in CPDS Analytical Development Belgium, where he leads the small molecule method development organization responsible for the development, validation and transfer of chromatographic, physico-chemical and spectroscopic methods. Additionally, his team is responsible for introducing and implementing Process Analytical Technology (PAT) and new analytical technologies.  

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Abstract:

The presentation will focus on following key aspects: the importance of PAT in the pharmaceutical industry, the translation towards JnJ and the different ways PAT can be implemented as part of the control strategy. This will be demonstrated by different case studies.  

Steve Ward-Smith

Malvern Panalytical

Bio:

Dr Steve Ward-Smith is a Large and Strategic Account manager in the food and pharmaceutical sector at Malvern Panalytical. He has a degree in Chemistry from Manchester University, a Masters in Biomolecular Technology from Leicester University and a PhD in Chemistry from Nottingham university. He has worked for Malvern Panalytical for 27 years. He is the Chair of ISO TC281 in Fine Bubble technology which covers the measurement and applications of nanobubbles and a Convenor of ISO TC24 SC4 in characterisation methods of materials (other than by sieving). 

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Abstract:

This talk will provide an overview on the key technologies currently used and under investigation as PAT tools within the pharmaceutical sector. A brief overview of how the technology works and potential strengths and weaknesses / applications which suit and which don’t will be given. 

Alan Ryder

University of Galway

Bio:

Professor Alan G. Ryder has a B.Sc. (1989) and Ph.D. in chemistry (1994) both from the University of Galway.  After working as a postdoctoral researcher in University College Cork, he joined the National Centre for Laser Applications in the School of Physics at the University of Galway as a postdoctoral researcher in 1997 to work on developing quantitative Raman spectroscopy-based methods for measuring illicit narcotics.  From 2006 to 2022 he was based in the School of Chemistry at the University of Galway.  In 2003 he formed the Nanoscale Biophotonics Laboratory (NBL) and the research group focusses on the use of photonics and chemometrics technologies for life and physical science applications.  In the Analytical Sciences, the primary emphasis is developing rapid, quantitative analytical methods for the analysis of complex materials with particular focus on biopharmaceutical manufacturing and he has collaborated with a range of global biopharmaceutical manufacturers on a variety of analytical research projects.  In May 2020 he started coordinating the large EU funded PAT4Nano project (www.pat4nano.com) which seeks to develop novel online methods for the analysis of nanosuspensions.  To date he has secured >11M€ of research funding, supervised to completion 27 Ph.D. and M.Sc. research students in both chemistry and physics, authored >100 publications, and generated 3 patents. 

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Abstract:

Raman spectroscopy is a well-established molecular characterisation tool with widespread industrial adoption in the pharmaceutical domain for small molecule reaction monitoring, crystallisation analysis, and the characterisation of Active Pharmaceutical Ingredients (APIs).  In most applications Raman is used to look at chemical changes, however, Raman can also be used to measure particle size and this has previously been demonstrated in very small nanoparticles (<~10 nm) for several inorganic materials.  Here we demonstrate how Raman spectroscopy can be used to extract size information from concentrated nanosuspensions with particle sizes in the 450–700 nm size range (Z-average).   

Concentrated API nanosuspensions (5A/5B) provided by Janssen were thermally degraded at 60°C to induce aggregation and the process monitored by Raman spectroscopy and the size measured by Dynamic Light Scattering (DLS).  The size increases (Z-average) were significant and reproducible, from ~475 to ~595 nm (5A) and from ~530 to ~670 nm (5B) over 5 hours. As particle size increased, light scattering efficiency increased leading to both an increase in the measured intensity of the Raman signal and small, yet reproducible spectral changes (observable in the normalised spectra).  These spectral changes correlate with nanoparticle size and one generate relatively simple chemometric models which correlate these changes with the reference size measurements from DLS.  This opens the possibility to use Raman as an online PAT tool for the simultaneous monitoring of chemical composition and particle size changes. 

Carl Schuurmans

InProcess-LSP

Bio:

Having previously worked at Philips research, Utrecht University, MIT, and Harvard, Carl is currently a senior scientist at InProcess-LSP. His research interests are pharmaceutical technology and process analytics, mainly focused on PAT-based particle size measurements.

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Abstract:

Spatially Resolved Dynamic Light Scattering (SR-DLS) is a recently introduced advanced process analytical technology for real time nanoparticle size measurements in flowing suspensions. The unique combination of measuring particle size in flowing suspensions and fast acquisition times allows detailed monitoring of process performance. For particle size monitoring of extremely highly concentrated nanosuspensions during nanomilling, SR-DLS configured with a recently developed Online Micro Dilution (OMD) device was applied successfully. Besides obtained real time DLS data the technology also offers highly informative imaging functionalities to detect a-typical large particles or agglomerates. The basic principles of SR-DLS and OMD will be discussed and several nanomilling examples will be shown.

Nicole Meulendijks

TNO

Bio:

Nicole Meulendijks is a Project Manager at the department Materials Solutions at the Dutch organisation of applied scientific research, TNO. She studied Chemistry at Higher Laboratory Education level in Eindhoven and obtained her B.Sc. degree in 2001. From 2001-2003, she worked as a research assistant at the Eindhoven University of Technology. Since 2003 she has been working at TNO, she has been active in the field of nanoparticle synthesis and formulation, surface modification and nanomaterial characterization. She is (co-) author of 18 publications, numerous conference proceedings and (co-)inventor of 7 patents, issued or pending.

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Abstract:

Nano formulations are a critical type of materials that can be found in a wide range of industrial applications e.g.  pharmaceuticals, inks, paints, and fine chemicals used in advanced manufacturing. Many of the specific materials used are produced by a milling process which is typically energy- and time consuming. Accurate measurement of nano formulations and the size of nanoparticles is critical for obtaining efficient manufacturing processes and ultimately the performance of materials. In the PAT4Nano project, nano-characterization tools are combined to enable the continuous, rapid, and reliable particle size measurements leading to an increased process efficiency and reduced production costs. In the project, real time process monitoring of pharmaceutical drug production processes is investigated. Measurement accuracy plays an important role during the manufacturing processes of pharmaceutical drugs where size and characteristics of nanoparticles can be used to produce more effective therapies.

Verification, validation and inter technique comparison of different PAT tools in the size reduction of particles to the nanometre range is an important aspect when introducing newly developed analytical tools. Most online analytical tools have several specific challenges in their application, the aim is to enable critical production decisions to be made following the use of the PAT tools. For this, it is crucial that the obtained data is reliable. Strategies for the verification of the developed PAT tools have been defined. It is shown that the application of on/at line nanocharacterization tools on a small scale milling process can be useful to follow the process from sub-micron start-materials into end products the nanorange in an automated manner. In the investigated process, sampling was performed automatically throughout the milling process. Laser diffraction and dynamic light scattering techniques were used as complimentary characterization tools in this study. The ability of such technologies to follow the milling process in real time and the comparability with traditional laboratory results will be demonstrated. 

Maxim Verstraeten

The Janssen Pharmaceutical
Companies of Johnson & Johnson

Bio:

Maxim Verstraeten obtained his Ph.D. in Pharmaceutical Technology in 2018 at the University of Ghent, Belgium, where he focused on Process Analytical Technology for Continuous Manufacturing of oral solids. Maxim joined Janssen Pharmaceutica in 2018 and is currently working as a Senior Scientist in Drug Product Development, ensuring the end-to-end development of various parenteral and liquid dosage forms within the small molecule portfolio of Janssen.

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Abstract:

Long-Acting Injectables (LAI) are gaining interest as they are an efficient delivery strategy enabling a reduced dosing frequency and hence increased therapy compliance. The design of such delivery system often relies on an aqueous suspension of a poorly soluble salt/prodrug, where top-down manufacturing approaches are applied to achieve the right particle size (in view of a proper pharmacokinetic performance). However, controlling this aseptic manufacturing step is very challenging as sterility requirements do not allow high-frequency In-Process Control (IPC) sampling. This creates unique opportunities for Process Analytical Technology (PAT), where in-line tools can replace IPC sampling and monitor the particle size throughout the size reduction step, removing the need for manual intervention. This presentation will present a case study where a PAT sensor is implemented in a sterile top-down manufacturing process.

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