Emerging applications and regulatory strategies for advanced medicines manufacturing - Towards the development of a platform approach.

The last decade has seen Advanced Medicines Manufacturing (AMM) progress from isolated product developments to the creation of industry-academic centres of excellence, regulatory innovation progressing leading to new standards, and product commercialisation across multiple product formats. This paper examines these developments focusing on successful applications and strategies presented at the 2023 Symposium of the International Consortium for Advanced Medicines Manufacturing (ICAMM). Despite these exemplar applications, there remain significant challenges to the sector-wide adoption of AMM technologies. Drawing on Symposium delegate expert responses to open-ended questions, our coding-based thematic analysis suggest three primary enablers drive successful adoption of AMM technologies at scale, namely: the ability to leverage pre-competitive collaborations to challenge-based problem solving; information and knowledge sharing through centres of excellence; and the development of AMM specific regulatory standards. Further analysis of expert responses identified the emergence of a 'Platform creation' approach to AMM innovation; characterised by: i) New collaboration modes; ii) Exploration of common product-process platforms for new dosage forms and therapy areas; iii) Development of modular equipment assets that enable scale-out, and offer more decentralized or distributed manufacturing models; iv) Standards based on product-process platform archetypes; v) Implementation strategies where platform-thinking and AMM technologies can significantly reduce timelines between discovery, approval and GMP readiness. We provide a definition of the Platform creation concept for AMM and discuss the requirements for its systematic development.

Rational and practical considerations to guide a target product profile for patient-centric drug product development with measurable patient outcomes - A proposed roadmap.

The increasing awareness of acceptability and usability of pharmaceutical drug products by the patient as a key quality requirement continues to drive need for integrating patient centric drug product design into the pharmaceutical development process. The complex matrix of multiple drug product related decisions during the early drug development process often limits patient-centric drug product (PCDP) design options in the final commercial drug product development phase. To integrate the specific needs and perspectives of patients into drug development and product design process, a rational approach integrated into the complex development matrix is required from the start and weighs product development decision options accordingly. The aim of this work was to develop a roadmap for PCDP design in a multidisciplinary approach that leads to better usability, adherence and acceptance of the drug by patients via early integration into the development matrix. The proposed rational approach is based upon regulatory requirements and lessons learned from pediatric and geriatric drug development.

Key acceptability attributes of orodispersible films.

The features rendering orodispersible films (ODFs) patient-centric formulations are widely discussed in the scientific literature. However there is a lack of research studies exploring ODF characteristics with a potential impact on end-user acceptability. The aim of this study was to identify the key ODF characteristics affecting end-user acceptability by developing in vitro test methods for the prediction of ODFs acceptability and correlate these formulation characteristics with the data obtained from a human panel study. Four drug-free single-polymer films were prepared by solvent casting. Solutions of poly(vinyl) alcohol (PVOH) 39 KDa (P1), PVOH 197 KDa (P2), carboxymethylcellulose (CMC) 395 KDa (C1), and CMC 725 KDa (C2) were prepared. Texture analysis and Dynamic Mechanical Analysis (DMA) were used to assess film tack. Petri dish and drop methods were used to assess disintegration time. A human panel of 24 healthy young adults was employed to identify end-user acceptability criteria of the four study film samples. Texture analysis data of ODF tack were not found to be in agreement with the in vivo perceived stickiness in the mouth. However, measurement of the area under the adhesive force curve obtained by DMA correlated with in vivo perceived stickiness data for all samples. The disintegration times obtained by drop method were more comparable to human panel data than the petri dish method. Hence DMA and drop methods proved to be promising methodologies for the prediction of the end-user acceptability. The type and molecular weight of the film-forming polymer had a strong influence on stickiness perception, whereas only polymeric molecular weight influenced perceived disintegration time. The human panel study showed that Participant Reported Outcomes (PROs) for the perceived stickiness in the mouth and disintegration time of test films received significantly different scores between samples, and thus were identified as the key attributes with the potential to affect the end-user acceptability. ODF stickiness and disintegration time should therefore be evaluated at an early stage of the drug product design.

Orodispersible films: Towards drug delivery in special populations.

Orodispersible films (ODF) hold promise as a novel delivery method, with the potential to deliver tailored therapies to different patient populations. This article reviews the current strides of ODF technology and some of its unmet quality and manufacturing aspects. A topic highlights opportunities and limitations of inkjet printed ODF as a population-specific drug delivery. Overall, this article aims to stimulate further research to fill the current knowledge gap between manufacturing and administration requirements of ODF targeting specific patient subpopulations such as geriatrics.

An in vitro and in silico study of the impact of engineered surface modifications on drug detachment from model carriers.

In silico modeling was used to predict the impact of carrier surface modifications on the in vivo plasma concentration of an active pharmaceutical ingredient (API) and as a tool to support formulation development. In vitro fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of salbutamol sulphate delivered from Cyclocaps®, detached from unmodified and surface engineered glass beads were measured using a Next Generation Impactor (NGI). Surface roughness was chosen to classify surface modification/engineering and it was evaluated via scanning electron microscopy (SEM) and image analysis. An in silico pharmacokinetic (PK) model was built and the quality confirmed with available literature data. Plasma profiles were generated combining the PK model with in silico deposition models for salbutamol sulphate released from Cyclocaps®, unmodified and surface engineered glass beads. The increased roughness of the surface of engineered beads resulted in a FPF 1.36 times higher than that of untreated beads. Cmax from the in silico plasma profile of salbutamol released from the surface engineered beads was 1.20 fold higher than that from untreated beads. Increasing the surface roughness was found to augment the amount of drug loading and detaching from the carrier both in vitro and in silico.

The effects of powder compressibility, speed of capsule filling and pre-compression on plug densification.

This paper describes the effect of powder compressibility and two process parameters of a dosator nozzle capsule filling machine on powder densification during plug formation. One process parameter was the ratio between the powder bed's depth and the length of the nozzle dosing chamber, hereinafter referred to as F. The other one was the speed of capsule filling. This paper demonstrates that powder densification during the capsule filling process is a function of the powder compressibility and the above process parameters (increasing them leads to higher plug density). The Walker model was used to characterize the compressibility of powders at low compression forces and the obtained compressibility coefficient W proved to be a good predictor of powder densification during the capsule filling process.

Application of QbD principles for the evaluation of empty hard capsules as an input parameter in formulation development and manufacturing.

Understanding the product and process variable on the final product performance is an essential part of the quality-by-design (QbD) principles in pharmaceutical development. The hard capsule is an established pharmaceutical dosage form used worldwide in development and manufacturing. The empty hard capsules are supplied as an excipient that is filled by pharmaceutical manufacturers with a variety of different formulations and products. To understand the potential variations of the empty hard capsules as an input parameter and its potential impact on the finished product quality, a study was performed investigating the critical quality parameters within and in between different batches of empty hard gelatin capsules. The variability of the hard capsules showed high consistency within the specification of the critical quality parameters. This also accounts for the disintegration times, when automatic endpoint detection was used. Based on these data, hard capsules can be considered as a suitable excipient for product development using QbD principles.

The effect of capsule-filling machine vibrations on average fill weight.

The aim of this paper is to study the effect of the speed of capsule filling and the inherent machine vibrations on fill weight for a dosator-nozzle machine. The results show that increasing speed of capsule filling amplifies the vibration intensity (as measured by Laser Doppler vibrometer) of the machine frame, which leads to powder densification. The mass of the powder (fill weight) collected via the nozzle is significantly larger at a higher capsule filling speed. Therefore, there is a correlation between powder densification under more intense vibrations and larger fill weights. Quality-by Design of powder based products should evaluate the effect of environmental vibrations on material attributes, which in turn may affect product quality.

Combining formulation and process aspects for optimizing the high-shear wet granulation of common drugs.

The purpose of this research was to determine the effects of some important drug properties (such as particle size distribution, hygroscopicity and solubility) and process variables on the granule growth behaviour and final drug distribution in high shear wet granulation. Results have been analyzed in the light of widely accepted theories and some recently developed approaches. A mixture composed of drug, some excipients and a dry binder was processed using a lab-scale high-shear mixer. Three common active pharmaceutical ingredients (paracetamol, caffeine and acetylsalicylic acid) were used within the initial formulation. Drug load was 50% (on weight basis). Influences of drug particle properties (e.g. particle size and shape, hygroscopicity) on the granule growth behaviour were evaluated. Particle size distribution (PSD) and granule morphology were monitored during the entire process through sieve analysis and scanning electron microscope (SEM) image analysis. Resistance of the wet mass to mixing was furthermore measured using the impeller torque monitoring technique. The observed differences in the granule growth behaviour as well as the discrepancies between the actual and the ideal drug content in the final granules have been interpreted in terms of dimensionless quantity (spray flux number, bed penetration time) and related to torque measurements. Analysis highlighted the role of liquid distribution on the process. It was demonstrated that where the liquid penetration time was higher (e.g. paracetamol-based formulations), the liquid distribution was poorer leading to retarded granule growth and selective agglomeration. On the other hand where penetration time was lower (e.g. acetylsalicylic acid-based formulations), the growth was much faster but uniformity content problem arose because of the onset of crushing and layering phenomena.

Formulation design for optimal high-shear wet granulation using on-line torque measurements.

An alternative procedure for achieving formulation design in a high-shear wet granulation process has been developed. Particularly, a new formulation map has been proposed which describes the onset of a significant granule growth as a function of the formulation variables (diluent, dry and liquid binder). Granule growth has been monitored using on-line impeller torque and evaluated as changes in granule particle size distribution with respect to the dry formulation. It is shown how the onset of granule growth is denoted by an abrupt increase in the torque value requires the amount of binder liquid added to be greater than a certain threshold that is identified here as 'minimum liquid volume'. This minimum liquid volume is determined as a function of dry binder type, amount, hygroscopicity and particle size distribution of diluent. It is also demonstrated how this formulation map can be constructed from independent measurements of binder glass transition temperatures using a static humidity conditioning system.