AGENDA

 Daniel MARKL

University of Strathclyde - CMAC

Reader in Pharmaceutical Product Engineering

Capping: ideas for a better understanding and prediction

Capping is a common defect that can occur during the manufacturing of pharmaceutical tablets. It refers to the separation of one or both cups of biconvex tablets. Despite being recognized since the early development of the tableting process in the 19th century, capping is still not fully understood and remains challenging to predict. 

In this presentation, we will discuss and attempt to comprehend the impact of process parameters on capping. Additionally, we will explore the product properties that can aid in predicting capping occurrences. 

 Jan Henrik FINKE

University of Braunschweig

Division Head Pharma and Bioparticle Technology

Determining important physical properties of drugs by compaction simulation

The development of a quality pharmaceutical tablet product is a complex process. Successful design of tablet formulation requires a clear understanding of mechanical properties of APIs, excipients, and their mixtures. Owning to the level of complexity, tablet development has been largely empirical. Consequently, a significant amount of active pharmaceutical ingredient (API) and a long time is required before identifying a scalable tablet formulation by a trial-and-error approach. However, problems still frequently occur during commercial manufacturing. There is a need for a material-sparing tool for characterizing compression properties of powders in order to improve the efficiency of tablet development in the pharmaceutical industry. With the aid of a compaction simulator, it is possible to systematically characterize APIs and formulations using little material, enabling an expedited and material-sparing development of quality tablet formulation. The ability of compaction simulation to predict success or failure of a prototype tablet formulation during commercial manufacturing has been well recognized. This talk will focus on the use of a compaction simulator as a tool to determine fundamental physical properties of powders, e.g., plasticity of powders and true density, which is an essential element for developing a materials database to enable digital tablet formulation design.

Driving timely clinical development: simulation-based process development and tech-transfer

With the ever-growing pressure to get new therapies to patients faster, predictive modeling and simulation tools are increasingly recognized as critical enabling technologies for accelerating drug product development. In the development of oral solid dosage forms, predictive modeling and simulation tools of the manufacturing processes can enhance process understanding, save on API supply, improve product quality, and reduce or eliminate many of the bottlenecks associated with empirical methods. 

Each API has its own set of unique physical and chemical properties that can affect the success of product formulations and manufacturing routes. Because of this, the manufacturing process for solid dosage forms need to be thoroughly understood. Determining robust formulations and processes for a given compound requires a deep understanding of material science and powder behavior.

This presentation will cover aspects of:

• Compaction Simulation and Discrete Element Methods (DEM) as advanced technologies that can be used for a wide range of applications including material characterization, formulation development, process scale-up and tech-transfer

• An accelerated and material-sparing approach that can expedite formulation, process development and improved product quality.

Johny BERTELS

Janssen, Pharmaceutical Companies of Johnson & Johnson

Senior Scientist

Concept of modern drug product development

Time to market and limited quantities of API are pressing aspects in early drug product development. By combining computer aided formulation concepts, with a systematic and scientific based working pattern, both aspects can be addressed successfully. The presentation discusses the benefits of such an approach.

Enabling material sparing technical transfer of tablets containing spray dried dispersions into an early phase clinical manufacturing setting via compaction simulation

Lonza recently established an early phase clinical manufacturing (EPCM) facility designed to quickly advance molecules to the clinic by enabling flexible and data-driven development and clinical manufacturing. Tablets containing spray dried dispersions (SDDs) for bioavailability enhancement are a common dosage form manufactured in EPCM. However, SDD tablets can be challenging to manufacture successfully “right first time” on a rotary tablet press due to the unique physicochemical properties of each SDD. Therefore, successful clinical manufacturing of SDD tablets has traditionally relied on conducting a ‘demonstration batch’ prior to clinical manufacturing to set processing parameters and avoid risks such as deviations and low yields. To reduce the time, resource, and material constraints, we have evaluated the STYL’One Evo compaction simulator as a time- and material-sparing alternative to a demonstration batch. By performing matching studies on the compaction simulator during demonstration batches and collecting data during EPCM batches a comparison of the two methodologies was evaluated. In the presentation the capability of the STYL’One Evo to be used as a predictive tool for clinical manufactures will be discussed.

 Sabine FRIEDLHUBER

MEGGLE

Head of Innovation & Formulation

Double API sourcing on commercial production: scale-down assesment using a compaction simulator

The purpose of this activity was to evaluate the impact, of using a new processed Drug Substance (DS), on the final product Critical Quality Attribute.

This activity therefore consisted in:

• Characterizing two lots of DS, current and new process, identifying their mechanical properties by performing a Heckel analysis and compression analysis.
• Manufacture tablets at R&D scale, by compaction and compression simulation, using the new processed DS supplier to compare the dissolution profiles of the finished product.

Andrew S.PARKER

MERCK

Senior Scientist

Avoiding tablet lamination - a troubleshooting case study 

Compaction simulation allows tablets formulation development and understanding of compression process in a material sparing way. In the present case study, tablet formulation showed tendency to lamination. Compaction simulation trials on a STYL’One Nano aimed at understanding how compression parameters like compression force and compression speed influence the lamination occurrence were performed. The trials lead to successful identification of air entrapment as the cause of lamination. The troubleshooting consisted in examining alternative tablets formulations and setting up compression parameters that would lead to defect free tablets. Finally, a set of trials to determine pre-compression and upper punch penetration settings to be used for manufacture of this product were successfully determined. The use of a compaction simulator contributed to robust formulation and process development without excessive material spending.

 Sergei TROFIMOV

Ashland

Pharmaceutical Scientist

Suitable powder characteristics of amorphous solid dispersions for direct compression obtained via spray drying

Globally, tablets remain the preferred oral solid dosage form because of its high stability, easy handling and easy dosing. Moreover, tableting by direct compression is a fast and “simple” process to produce a high amount of tablets. However, direct compression of powders is in many cases not straightforward, since most of the powders do not exhibit preferred powder/particle characteristics to obtain proper powder compacts, which might result in tablet deficiencies (e.g. tablet capping and lamination). Consequently, intensive and time-consuming formulation and/or process development is required (e.g. intermediate granulation step to improve powder quality).

Via spray drying, solid particles are formed by atomizing a liquid feed in a drying chamber. Therefore, particle shape/size can be adjusted by applying varying process parameters (e.g. nozzle type, atomization gas, inlet air temperature, inlet airflow). This implies that spray drying can be used as particle engineering technology to target specific particle and powder characteristics.

Powder characteristics which are of importance to obtain proper powder compacts are mainly (i) powder flowability and (ii) powder compressibility. Proper powder flowability is required to result in an adequate die filling, which is critical to obtain a robust compaction process (i.e. low tablet mass variation). Moreover, powder flowability is correlated to the particle size distribution (since – in general – larger particles result in better powder flow) and to particle shape.

Furthermore, sufficient powder compactability is required to result in proper bonding, and so, in good tablets. Powder compactability can also be influenced by particle shape (wrinkled vs. inflated particles) and by particle size (small particles have a larger specific surface area compared to larger particles).

Current study shows the ability to obtain the required powder characteristics via spray drying to directly result in feasible powder properties for tableting via direct compression.

 Friederike GUETTER

KORSCH

Process expert

Kinetic considerations of tableting fluidized bed granulated living microorganisms

The production of tablets containing viable microorganisms is of particular importance for the effective administration of probiotic microorganisms. Previous studies have investigated the influence of formulation and compression stress in particular, and have linked deformation mechanisms to cell damage. The question of how other process parameters affect the survival of microorganisms during tableting remains open. Especially for industrial scale production, the speed of tableting is of crucial importance. Using a Styl’One Evo, the influence of dwell time and consolidation time on the survival of fluidized bed granulated yeast cells and on the physical-mechanical tablet properties was investigated and related to formulation-specific deformation characteristics.

 Susanne MUSCHERT

University of Lille

Associate Professor

Simulation of a roller compaction by combination of a compaction simulator and oscillating mill - a sparing approach

This study developed a material sparing approach for process development using a compaction simulator and oscillating mill to mimic a roller compactor. Results showed that the compaction simulator and oscillating mill adequately mimicked the roller compactor, saving material and time during process development.

Ariana LEON

Nanjing Haiwei Pharmaceutical Technologies

Scientist

Successful development of a Directly

Compressible Mannitol for high-speed production on a compaction simulator

Mannitol is the first intention excipient choice for API’s with stability problems in final drug formulations. Mannitol is not hygroscopic, presents a high chemical stability and is considered as compatible with almost all drugs. Texturized mannitol powders have been developed specifically for direct compression processing, enabling the easy tableting. However, whatever the process and parameters used to produce directly compressible mannitol, and whatever the compactibility of this mannitol, lamination (usually described as capping by formulators) is observed at high tablet production speed on industrial equipment, particularly when producing convex tablets.

Mannitol behavior is evolving with the tableting speed. This capping appears only at high tableting speed and the necessity to study this phenomenon on industrial rotary press has been a drag for a long time. Rotary tablet press simulators STYLCAM and STYL'One Evo made it possible to test numerous mannitol powders mimicking high speed production and finally, to understand how the mannitol structure interferes with the observed capping phenomenon. A new directly compressible mannitol, PEARLITOL® 200 GT, was developed. Studies with sitagliptin as drug model demonstrated that delaying the apparition of capping presents huge interests in tablet formulation, by decreasing the tablet size by one third thanks to an API ratio increase of fifty per cent, and in tablet production, by increasing the production yield by fifty percent.

Karl WAGNER

University of Bonn 

Professor for Pharmaceutical Technology

Day 2

MEDELPHARM'S FACILITIES, BEYNOST

• 8:00 am : Pick-up by bus from Lyon
• 8:30 am:  Welcome coffee 
• 9:00 am:  Start of presentations
• 12:30 pm.: Lunchbreak & networking time
• 2:00 pm: Continuation of talks 
• 6:00 pm:  Wrap-up and departure to Lyon (*)
• 7:00 pm:  Enjoy a cruise aboard the Hermes II to discover the beautiful city of Lyon!

(*Transportation to Lyon and dinner costs courtesy of MEDELPHARM)