Commentary on the EMA reflection paper on the pharmaceutical development of medicines for use in the older population.

Older people are often affected by impaired organ and bodily functions resulting in multimorbidity and polypharmacy, turning them into the main user group of many medicines. Very often, medicines have not specifically been developed for older people, causing practical medication problems for them like limited availability of easy to swallow formulations, easy to open packaging and dosing instructions for enteral administration. In 2020, the European Medicines Agency (EMA) published a reflection paper 'Pharmaceutical development of medicines for use in the older population', which discusses how the emerging needs of an ageing European population can be addressed by medicines regulation. The paper intends to help industry to better consider the needs of older people during pharmaceutical/clinical medicines development by summarising data on the most relevant topics, providing early suggestions on how to move forward and prompting expert discussions and studies into knowledge gaps. Topics include patient acceptability, (dis)advantages of an administration route, formulation, dosage form, packaging, dosing device and user instruction. While the paper is directed at older people and the pharmaceutical industry, the reflections are also relevant to younger patients with similar disease-related needs and of value to other stakeholders parties, e.g., healthcare professionals, academics, patients and caregivers, as the paper makes clear what can be expected from industry and where collaborative work is needed. This commentary provides an overview of the different steps in the development of the reflection paper, discusses points considered most controversial and/or subject to (multidisciplinary) expert discussions and indicates their value for real world clinical practice.

Studies of the crystallization of amorphous trehalose using simultaneous gravimetric vapor sorption/near IR (GVS/NIR) and "modulated" GVS/NIR.

The purpose of this research was to investigate the influence of changes in the amorphous state on the crystallization of trehalose. Amorphous trehalose is known to stabilize biomaterials; hence, an understanding of crystallization is vital. Amorphous trehalose, prepared by spray-drying, was exposed to either a single step (0-75%) in relative humidity (RH) or to modulated 0-75-0% RH to cause crystallization. For the single-step experiment, two samples crystallized in a predictable manner to form the dihydrate. One sample, while notionally identical, did not crystallize in the same way and showed a mass loss throughout the time at 75% RH, with a final mass less than that expected for the dihydrate. The idiosyncratic sample was seen to have a starting near infrared (NIR) spectra similar to that exhibited by anhydrous crystalline trehalose, implying that short-range order in the amorphous material (or a small amount of crystalline seed, not detectable using powder X-ray diffraction) caused the sample to fail to form the dihydrate fully when exposed to high RH. The modulated RH study showed that the amorphous material interacted strongly with water; the intensity of the NIR traces was not proportional to mass of water but rather the extent of hydrogen bonding. Subsequent crystallization of this sample clearly was a partial formation of the dihydrate, but with the bulk of the sample then shielded such that it was unable to show significant sorption when exposed to elevated RH. It has been shown that the nature of the amorphous form will alter the way in which samples crystallize. With oscillation in RH, it was possible to further understand the interactions between water and amorphous trehalose.

Adjusting and understanding the properties and crystallisation behaviour of amorphous trehalose as a function of spray drying feed concentration.

Trehalose is known to stabilise proteins and peptides in the amorphous state. It is believed that crystallisation to a dihydrate is an important aspect of this protection, with trehalose acting as a desiccant to keep water away from, and prevent damage to, the biomolecules. The structure of amorphous materials has an impact on their ability to crystallise (possibly due to the presence of different amounts of short range order). In this study, repeat batches of trehalose were spray dried from different solution concentrations in water (0.5, 5.0 and 10.0% w/v). Each feed concentration resulted in amorphous spheres. Those from the highest feed concentration were found to be the largest particle size (due to more rapid onset of drying) whereas the lowest feed concentration resulted in the smallest size. The high feed concentration resulted in material that reproducibly and readily crystallised when exposed to water vapour, however the excess water (that over and above the amount needed to form the crystalline dihydrate) was not readily desorbed, presumably as it was entrapped between the recently formed crystals. The most dilute feed concentration resulted in samples that exhibited great variability between batches, often requiring a larger mass of water to be sorbed before the crystallisation would begin than was needed for samples from higher feed concentrations. The exception to this was one batch that was observed by NIR to have the aspects of crystalline structure in its amorphous state (presumably due to longer drying times allowing some short range order). Whilst these samples allowed desorbed water to clear the crystallised material more readily than was observed from higher feed concentration samples, the variability was a perceived disadvantage. A reasonable compromise was the material formed from intermediate feed concentration which showed less variability than seen for low feed materials and greater dissipation of desorbed water than for high feed material. It is concluded that the properties of amorphous trehalose are altered as a consequence of processing and care must be taken to optimise this when attempting to stabilise macromolecular drugs.