INFORM 2020 - Molecules to Manufacture: Processing and Formulation Engineering of Inhalable Nanoaggregates and Microparticles

Lung diseases are a major global health burden. 300 million people live with asthma worldwide and it is predicted that chronic obstructive pulmonary disease will become the third-leading cause of death by 2020. The inhalation of therapeutic aerosols is a familiar medical strategy to treat lung diseases. Aerosol therapy can also achieve high antibiotic concentrations in the lung to treat infections. When aerosols are targeted into the deep lung, inhaled therapy also provides a means to achieve systemic concentrations of active pharmaceutical ingredients and avoid the need for injections of drugs that are destroyed in the gastrointestinal tract, such as insulin. Despite its potential, many patients fail to gain the full benefits of inhaled therapies in treating lung disease, and systemic drug delivery has failed to achieve the market break-through it deserves. Some of the ineffectiveness arises from the inability of patients to use their therapy correctly. However, achieving aerosol deposition in the lungs is a major challenge even for those patients with good inhaler technique.

The challenge is to produce a portable dosage form containing components that can be redispersed by a patient. Redispersion must be achieved with uniformity of a dose in the form of an aerosol with the properties required for lung penetration. Turning potentially inhalable particles into formulated products that can be manufactured reproducibly, and that achieve consistent aerosolization performance between different patients poses many challenges that are poorly-solved. Consensus meetings of industrial, academic and regulatory experts in the field of inhaled medicine have identified the need to improve control and consistency of drug deposition performance. Additionally there is a need to improve our understanding of how and why the characteristics of starting materials interact with the manufacturing conditions to lead to inter-batch and inter-patient variability in aerosol characteristics. At the heart of the challenge is the fact that the very property of the particles that makes them suitable for inhalation (their small size which, at less than 5 microns, is less than the diameter of a human hair) also causes them to clump together as agglomerates.

Theme 1 of the project will employ synthonic engineering (a computer modelling technique based on the molecular structures of pharmaceutical ingredients) to achieve new abilities to predict agglomeration behaviour early in development, and the interactions of agglomerate materials with inactive ingredients in the formulation. Theme 2 will use new measurement techniques that image how agglomerates interact with each other in powders to develop an understanding and characterize how the agglomerate phase in a formulation leads to inter-patient or inter-batch variability of product performance. Theme 3 will underpin the knowledge gained from powder imaging to assess the underlying causes of agglomeration. Better, integrated experimental measurement techniques will be developed to characterize the material properties that regulate the extent and strength of interactions between particles. Theme 4 focuses on developing new computational models to characterize the behaviour of agglomerated powders during the mechanical processes occurring when a patient breathes through an inhaler, and when powders are processed during manufacturing. The final component of the project is to integrate the knowledge gained in Themes 1-4 to engineer quality into a range of test products selected by an advisory panel. This will be achieved by using the prediction and measurement techniques to inform formulation scientists, device designers and process engineers of the steps that are appropriate to mitigate the effects of agglomeration on product performance. The ultimate goal is to use the techniques developed to translate the therapeutic benefits for patients using inhaled medicines from molecules to manufactured products.

This research has the goal of improving our understanding of the formulation design, manufacturing processes and product performance of particulate inhalation products. The INFORM 2020 consortium aims to deliver a research program that expands the fundamental scientific understanding of the properties, formulation options and critical manufacturing process parameters to improve manufacturability of nano- and microparticle therapies. It is anticipated that the earliest research impacts could be in the treatment of lung diseases, which have major societal and economic effects. This will be achieved by improving the performance of existing therapies, but also supporting innovator industries by streamlining development cycles to bring novel drug candidates to the clinic.

Societal: Lung diseases are significant causes of mortality and morbidity in the UK with far-reaching societal impacts. Almost 30,000 people in the UK died from chronic obstructive pulmonary disease (COPD)-related conditions in 2010 [1], and COPD results in 1-in-8 hospital admissions [2]. COPD is expected to be the third-leading cause of death globally by 2020 [3]. An estimated 300 million individuals worldwide are affected by asthma [4] and asthma deaths exceed 180,000/yr worldwide [5]. With 250 million daily adjustable life years lost to asthma [4] asthmatics have increased risk of joblessness and reduced earnings. Improving the performance of therapies in this project and providing the means to develop new difficult-to-deliver (bio)pharmaceutical and high dose therapies for clinical use, would lead to improved quality of life for many.

Economic: Improvements in clinical treatments could bring significant economic gain by reducing the costs to the health service and the wider economy of ineffective treatment. The combined direct and indirect cost of COPD to the National Health Service is £1 billion per annum [6], whilst the costs of asthma are estimated at £750 million [7]. The impact on the wider economy is also substantial, e.g. 12.7 million workdays are lost annually to asthma symptoms costing £1.2 billion [8]. For the industry, the improved process understanding could decrease the material, manpower and facilities waste caused by poor process control, which is anecdotally as high as 50 % [9]. Additionally, better understanding of raw material behaviour and process engineering could, shorten development cycles and maximize the economic rewards of patent exclusivity.

Scientific: the global pulmonary drug delivery market was valued at $21.0Bn in 2012 and is expected to grow at 4.5% over the life of this project reaching a value of $28.7Bn in 2019 [10]. This project will improve understanding of the science of particle formulation and manufacture that have been acknowledged as scientific barriers to development. The project aims to advance predictive, measurement and characterisation sciences that can be applied by the pharmaceutical industry to help maximize the development new therapeutic entities and realise the potential market growth. This scientific impact would also extend beyond pharmaceutics to other industries (e.g. agrochemicals and construction materials) which also involve the creation, handling, stabilization and end-product manufacture of microparticulate materials.

[1] WHO statistics (2011); [2] European Respiratory Society (2011), An International Comparison of COPD Care in Europe; [3] Gartlehner et al. Annals of Family Medicine 4 (2006) 253-262; [4] Global Initiative for Asthma (2011), Global Strategy for Asthma Management and Prevention [5] Viegi et al. Euro. Resp. Mono. 8 (2003) 1-25; [6]; National Collaborating Centre for Chronic Conditions, Thorax 59 (2004) 1: i1-232; [7] Ayres et al. Thorax 66 (2011) 128-133; [8] Asthma UK, (2004) Where Do We Stand? Asthma in the UK today; [9] Rathore and Winkel Nature Biotech 27 (2009) 26-34; [10] Transparency Market Research "Pulmonary Drug Delivery Systems Market" (2014).