Deep Breaths and Dry Powder

Craig Davies-Cutting, Director of Inhaled Product Technology at Catalent, has spent his almost 30-year career in inhaled product formulation and development, whereas the career path of Carole Evans, Catalent’s Director of Inhalation Business Operations, includes a stint in health education before moving to aerosol development in the US, where she has been ever since. But what’s so great about inhaled drug delivery? Davies-Cutting is clear, “With tablets, the drug has to go through absorption and metabolism, so only a small proportion of API may be bioavailable. For local diseases like asthma, however, pulmonary delivery puts the drug right where it’s needed. You can use lower doses and get fewer side-effects.” And inhaled delivery has potential beyond airway disease – for example the nasal route has the potential to permit systemic or CNS-targeted delivery across the blood-brain barrier. “Rapid absorption through the nasal cavity means rapid onset – ideal for applications such as pain relief,” says Davies-Cutting. 

A world of unintended consequences

The flip-side of inhaled drug delivery is its developmental complexity. “You have to optimize the individual features of both device and formulation, and also their interplay,” states Evans. A metered dose inhaler product comprises the formulation, the container closure that meters out the formulation, the actuator that aerosolizes the metered aliquot, and often now a dose counter – and altering any one of these can create unexpected complications. Evans reminds us of the results of switching from chlorofluorocarbons (CFCs) to hydrofluoroalkanes (HFAs), a transition that started twenty years ago. “The change in the propellant necessitated valve modifications in terms of different elastomers and lubricants. We live in a world of unintended consequences,” she says.

Furthermore, the variable delivery seen with some inhalers, and the flat dose response curve typical of many topical drugs, results in significant subject-to-subject variability. Therefore, statistically relevant data requires large numbers of patients, resulting in long, costly trials. And beyond these technicalities is the human perspective. “The world’s best inhaler is useless if the patient doesn’t use it effectively,” says Davies-Cutting. “You must consider the real-world use of a product to make it as easy as possible for patients to take in the right way. Prescribing an inhaler that is suitable for the patient, and training them to adopt the right inhalation technique is key to therapeutic success.”

Guides for the guidelines

The hurdles in developing inhaled products are illustrated by a stark fact; there hasn’t been a generic inhaled product launched in the US market since 1996. Davies-Cutting believes that regulatory complexity is a contributory factor. The FDA applies the ‘weight of evidence’ approach – requiring data showing that the product is bioequivalent, but the details of bioequivalence requirements haven’t always been clear. To make matters more confusing, the European Medicines Agency uses a different approach (a ‘tiered approach’). Recently, however, the FDA has published new guidance, which Davies-Cutting hopes will provide more clarity on the US regulatory expectations for generic inhaled products. This presents a huge opportunity given that many respiratory disease drugs are off-patent in the US, or soon will be.

Evans believes that her background in health education helps her guide customers through the regulations. She suggests that regulators increasingly recognize the significance of formulation-device interactions, noting the requirement to label nebulized solutions with the nebulizer used in trials. “Years ago, you could use almost any marketed nebulizer for an inhalation solution product, but now it’s known that the nebulizer can affect clinical outcome,” says Evans.

Similarly, for metered dose inhalers, components used in trials are retained through development. Therefore, companies should pick their device early and wisely because changing device vendor is not trivial. “Switching your delivery device may require additional trials, perhaps even Phase III studies,” says Evans, “so you need to decide on your product profile early in development and be clear on the implications of the required dose – dry powder inhalers (DPIs) are better suited to large doses than metered dose inhalers (MDIs).” It is also important to understand the user perspective; a daily, self-administered treatment should be easily portable, suggesting an MDI or DPI, whereas portability isn’t as relevant to an emergency room treatment, where a nebulized solution would be acceptable.

A sniff of the future?

Looking ahead, Evans predicts new materials for inhaler devices and product labels that specify the device used in development. She also notes the improvements in valve and particle technologies that are leading to renewed interest in HFA formulations. Davies-Cutting suggests that the recent emphasis on the human, ‘voice of the customer’ perspective will continue. “Deployment of smartphone apps to monitor treatment is an area to watch,” he predicts. He also hopes to see in vitro tests that truly reflect the in vivo situation, and which will therefore be acceptable to the regulators. He points to recent work testing the effect of oropharyngeal geometry on drug delivery, and developing models of drug permeation and dissolution in lungs. “We’re reaching for the holy grail of in vitro-in vivo correlation,” he says.

But approval is still a high hurdle to jump, Davies-Cutting warns that “generic development can be as complicated as innovator development,” but it is also this complexity that attracts people like Davies-Cutting and Evans. “You’ve got the formulation, the device, the human interface – it’s not like popping a pill, and that’s what makes it interesting,” says Evans.

The inhalation market is big ($35-40 billion), but it’s still growing, and will continue to be served by both MDIs and DPIs. Much of the market comprises topical pulmonary drug delivery for respiratory diseases like asthma and COPD – which may soon become the second most common cause of death – but we’re also seeing growing interest in delivery to the nasal cavity for systemic effect.

For Catalent the creation of integrated solutions, from development to device and to market is our priority. Increased prevalence and diagnosis of respiratory disease is driving geographic expansion of our business, particularly in Latin America and Asia, but the company is also supporting innovation in the delivery of systemic therapies, and in the optimization of the drug/device interface that’s so critical to effective delivery. Fortunately, we have years of experience in formulation development and advanced delivery technologies, and clinical and commercial manufacturing of both drugs and devices. From an infrastructure perspective, I think we now stand alone; we work across all inhalation dosage forms, manufacturing liquid and suspension products in a blow-fill-seal format, we have clinical and commercial capabilities for MDIs, clinical capabilities for dry powder applications, and we’re also in the process of creating commercial capability for unit dose and bi-dose nasal opportunities. We have a significant team of people supporting our inhalation development and manufacturing, almost all of whom have come out of pharma – some with over 30 years’ experience in fields from solid state chemistry to commercial manufacture. And we’re making further investments too; for example, we’re evaluating a platform technology for the manufacture of dry powder inhaler capsules for unit dose devices – both refillable and disposable.

A significant part of our business is developing dosage forms for non-invasive systemic nasal delivery, which is proving to be an acceptable approach for a wide range of products. Compared to dosage forms that are most familiar to consumers, such as loosely compressed tablets, developing an inhaled product is difficult and time-consuming. You have to invest significantly and accept that payback may take a number of years, so it’s not a business for the faint of heart. You have to be committed.