MG2 and RCPE: When Industrial Experience Embraces Scientific Thinking

26.11.2015

In 2011 MG2 started a partnership with the Research Centre of Pharmaceutical Engineering (RCPE) of Graz, to conduct advanced studies on powder properties and technological behaviour on MG2 capsule fillers.

In 2011 MG2 started a partnership with the Research Centre of Pharmaceutical Engineering (RCPE) of Graz, to conduct advanced studies on powder properties and technological behaviour on MG2 capsule fillers. The aim is the development of a validated predictive model suitable to help MG2’s customers in the optimisation of the dosing process of their products.

Since 2011 MG2 has started a scientific collaboration with the Research Centre of Pharmaceutical Engineering (RCPE). RCPE GmbH is an interdisciplinary research institute in the area of pharmaceutical process and product development in Graz. RCPE focuses on the development and production of pharmaceuticals using rational, science-based methods derived from a mechanistic understanding of relevant phenomena at all scales. Aim of this collaboration is to develop a science-based knowledge space to understand powder properties and to predict the technological behaviour of powder with MG2’s dosators for the production of capsule dosage forms. An initial predictive model was developed during the first phase of collaboration, the next phase of collaboration will now lead to the development of validated predictive model suitable to help MG2’s customers in the optimisation of the dosing process of their products.

The reference scenario: the protagonists of the story
The project arose from the need of relevant pharmaceutical companies, customers of MG2, which expressed interest in better understanding the relations between powder properties and dosators systems, to improve process knowledge and optimise the dosing of drugs into hard shell capsules.
RCPE as Competence Centre in the field of pharmaceutical Engineering Science has been identified as the right partner to support this strategic implementation phase of MG2.
The scientific collaboration has been designed to deliver a predictive model based on the physico-chemical and physical properties of the bulk to be dosed. The predictive model offers an effective support in identifying the most suitable dosing system based on a mechanistic understanding of the engineering parts and materials involved in the pharmaceutical process application.
MG2 strengthened its ability in processing control and predictive tools, it also extended its internal capabilities in R&D staff by recruiting a pharmaceutical chemist.
 
Purpose of the project
The main purpose of the scientific collaboration was to promote a dialogue between pharmaceutical science and the mechanical engineering area. Typically pharmaceutical companies mainly focus on product clinical performances and regulatory requirements while in contrast, machine manufacturers mainly focus on the technological features and processing controls. RCPE built a “bridge” between these two dimensions, providing its considerable scientific expertise and consolidating knowledge to cooperate with industrial partners from both pharma and the equipment side.
This scientific collaboration has been progressed by combining the extensive knowledge of MG2, specifically gained in the field of capsule fillers and dosators systems, with a structured scientific program deployed by RCPE’s scientists.
Outcome of this approach is the possibility to predict and select the most suitable dosator system based on the physical and/or physico-chemical profile of pharmaceutical materials, therefore the ability to design and to develop pharmaceutical process application in compliance with modern requirements, such as the Quality by Design guidelines.

Powder dosage and relevant critical issues
When filling pharmaceutical powders into capsules for usage in dry powder inhalers (DPI) several challenges have to be considered. DPIs as a dosage form consist of a powder formulation designed to deliver an active pharmaceutical ingredient (API) to the respiratory tract. These formulations are filled into hard-gelatine capsules that are pierced by the inhaler device directly before application. In order to reach their target size the tiny airways of the lung, API particles have to exhibit an aerodynamic diameter of 1–5 µm. Particles of this size are rather cohesive, show poor flowability and are generally administered in very low doses, i.e., in the range of a few micrograms. Thus, the handling and processing is rather difficult. In order to improve the flowability and dosing accuracy and to minimize dose variability, carrier-based formulations are used. These carrier-based formulations, also called binary formulations, consist of adhesive mixtures of the API attached to the surface of coarser carrier particles (bulking excipient). During inhalation, the API particles should detach again from the carrier to reach its target site, the deep lung. Otherwise, the API will impact in the upper respiratory tract together with the coarse carrier particles. Individual doses of carrier-based formulations need to be filled into capsules where the dose range for DPI capsules is low, i.e., in the range of a few milligrams. Moreover the capsule shell itself has to be handled in an appropriate way, as its performance during capsule filling, as well as within the inhalation device, is strongly affected by external factors, like humidity.
The final product performance is determined by material attributes, which are determined by molecular, particulate and surface properties. Hence, it is crucial to characterize and understand the critical particle, powder and compact properties of granular materials that will influence product development and performance.

Methodology employed
The project started with the analysis of the most recent scientific publications concerning the characterisation of powders for encapsulation. Then, several measurements and analyses were carried out on a wide range of powders, in order to compile a list of material attributes, i.e., scientific parameters defining the powders to be dosed. At the same time, thanks to MG2’s experience, it was possible to identify which machine settings can influence the process performance. Information concerning powder characterisation along with those concerning process parameters were used to structure a DOE approach (Design of Experiment): a systematic method to determine the relationship between factors affecting a process and the output of that process. It is used to find cause-and-effect relationships to manage process inputs in order to optimize the output. In the specific case, the DOE aimed to find correlations between 3 categories of inputs: powders’ characteristics (flowability, density, dimension of particles etc.), machine parameters (dosator’s diameter, rotation speed, dosing chamber etc.) and environmental conditions (humidity, temperature etc.), and measuring the dosing quality (amount and variability) as the output.

The development of a predictive process suitable to be repeated on all MG2 machines
To carry out these studies, MG2 provided to RCPE a capsule filler, i.e., lab-scale model Labby: a small unit with all features of industrial capsule fillers for pharmaceutical productions, manufactured by the Bolognese company. The same tests were performed on production machines, obtaining the same results, thus demonstrating the scalability of RCPE’s model. Consequently, MG2 can offer to its customers a full service for process optimisation, from R&D phases up to production. Thus, MG2 increased in a tangible manner its expertise that is an essential asset for developing and designing new machines and solutions for its customers.
MG2 in collaboration with RCPE is now ready to support its customers during: feasibility, optimization, scale up and technology transfer phases; offering services such as: powder and bulk characterization and/or profiling, prediction of weight variability and suitability of dosators systems, Design Space definition and Risk Assessment.