In the interests of speed, there can be a belief that the choice of device should be firmly established right at the beginning of a project, taking the view that this will reduce the requirement to repeat certain pieces of work or the number of modifications that may be required to the system later on. However, in practice, the fastest and most cost-effective route through the development pipeline may actually be to start out using one delivery technology platform, and switch to another commercially-representative platform later on.
Each individual program should be carefully considered, with all the technical characteristics and commercial constraints taken into account before the device is selected for each step on the development pathway, and it is important to bear in mind that there is no one-size-fits-all solution for every project. Generic programs, for example, may have additional constraints in terms of regulators requiring the originator device and formulation to be meticulously reverse engineered, and this may preclude any kind of mid-development switch. A novel drug substance would typically have no such constraints, but they do have a much higher risk profile, so the best approach is usually to try to maximize the probability of success (PoS) using the fastest, lowest cost approach, and then as the asset traverses key milestones, increases PoS and gains in value, to then switch to a more commercially-representative delivery platform. With generic medicines, there is already 100% confidence that the molecule is safe and effective, so it makes much more sense to start the development with the intended formulation and device technology approach.
Each main device platform type (pMDI, DPI or nebulizer) in turn has a myriad of associated formulation and device options that need to be selected, and each of these can affect the performance of the final drug–device combination. A DPI for example, could contain a dry powder formulated via spray drying, or a more traditional micronized drug and lactose blend. A multi-dose device might be selected, or a unit-dose device could be chosen, and in the case of the latter, there is the additional choice of a variety of capsule-based inhaler types or a unit-dose blister device, and there are devices within different air flow resistances and this factor can also influence performance. A further layer of choice comes with the various options for the user interface (the different steps the patient must take to use the device properly), which can have a profound effect on how easy it is for the patient to use their inhaler, and how successfully they receive their medicine to the appropriate region of the lungs. Choosing the right device for the intended patient group can have a major impact on whether the patient chooses to take their medicine at all, so the choices made are hugely influential in determining the ultimate success of a medicine.
It is important that all the possible formulation technologies and delivery devices are considered at the outset. The first decision will be whether the combination of molecular factors, intended patient group or stage of development drives a pMDI, a DPI, or a nebulizer as the most appropriate delivery system.
The pMDI is a familiar, low-cost device that patients generally find straightforward to use. These devices usually give moderate lung deposition but, in contrast to the DPI, the dose range is usually much more limited, and as a reservoir system it is also inherently quite wasteful. Such a device is, therefore, unlikely to be the best option for an expensive biologic drug, or one that requires a high dose (>1 mg).
If a unit-dose blister or capsule DPI is chosen, these can offer good lung deposition plus it can be straightforward to vary the dose in the early stages of development, simply by altering the weight of the formulation fill, or by getting the patient to take multiple individual doses. It is also flexible in terms of the type of formulation it can deliver in high doses with good aerosolization. However, there is little opportunity for a commodity unit-dose capsule device to confer intellectual property protection. A further drawback is the relative complexity of the user interface, but this may be less of an issue in the very early stages of development, where the medicine is only being taken under very controlled conditions.
Multi-unit dose DPIs have really established themselves as the standard of care in the asthma and chronic obstructive pulmonary disease (COPD) market, being portable, simple and quick to use, and typically, carrying a whole month’s therapy in a single device. Their intellectual property protection potential is usually much stronger than for the unit-dose capsule alternatives as well.
While nebulizer devices themselves may cost more than a DPI or a pMDI, (especially if a smart nebulizer is selected), the overall cost of pursuing this approach in the earlier stages of development can still be lower because the formulation process is often simpler and consumes less material. This can be especially true for biologic drugs, so it can still turn out to be the best option even though the delivery time will be longer than for a DPI. Its flexibility in terms of dose range is much greater, and, as previously mentioned, it can be easier to formulate, particularly if the drug has good solubility in water. A smart nebulizer can also provide very high levels of deep lung deposition and highly efficient delivery with minimal waste. This consistency and efficiency in deep lung delivery may help to contribute to a higher likelihood of success in early clinical development.
Picking the optimal device
The first consideration when selecting the best device platform and formulation combination will always be what is most compatible with the drug substance for delivery. Whether the drug substance is a small molecule or a biologic may also affect the choice, as will key physical properties such as solubility in water. Practical considerations, such as the likely age range of patients, may also be early considerations; elderly and very young patients are more likely to have dexterity issues, and may find devices with a complex user interface more difficult to use. The pMDI, for example, is superficially very easy for patients to use, but pMDIs can actually be difficult to use well because of the need to carefully coordinate the point of actuation during the inhalation.
It is also important to consider whether the drug is likely to be administered in a hospital setting, or at home, and if it is to be the latter, is the device sufficiently portable to fit in with the patient’s lifestyle? The dosing regimen will also need to be thought about, as well as the target deposition site within the lungs. If the device chosen does not meet the aims of the drug or the lifestyle of the patient, then patient adherence may be negatively affected, both in clinical trials and once the medicine has gained approval.
Cost implications will also need to be judged: while in the early stages of development an expensive device may be less of an issue, but once a product reaches the market, higher device costs may be acceptable in situations involving a niche disease and small patient numbers where lung delivery efficiency of an expensive drug may be paramount. However, for a very high-volume product containing a low-cost API and where moderate drug deposition may be perfectly acceptable for a drug with a very wide therapeutic index, high device costs are less acceptable.
It is also important to understand the long-term strategy for the company developing the medicine, for example, whether the final commercialization of the product is going to be done in-house, or if the company’s plan is to license the medicine to a commercial partner after Phase 1 or Phase 2. If the development strategy is the latter, then cost, speed and maximizing the probability of success are likely to be more important factors in the decision than giving detailed thought to the final commercial presentation. In contrast, with a generic, cost will be a critical consideration from the outset, as will getting into a final commercial presentation equivalent to the originator product, depending on the regulatory filing strategy.
This goes to the heart of the decision-making process. It is important to remember that the delivery device selected in Phase 1 does not have to be the same as the final commercial product. Rather, it needs to be phase appropriate. This will allow the early stages of development, particularly up to proof-of-concept, to progress as rapidly as is feasible, maximizing the probability of success and potentially generating value, before moving on to the development of the more involved and expensive phase of developing the final commercial product, once there is more confidence that the medicine can achieve commercialization.
Of all the considerations, some are more important than others. Clearly, this list is topped by technical considerations: if the drug’s properties are incompatible with a particular formulation or a device, it will be a non-starter. An antibody drug is unlikely to be stable when delivered via jet nebulizer, for example, and a drug given in doses in excess of 1mg would most likely preclude a pMDI.
At the other end of the spectrum, a molecule that is stable in solution and dissolves readily will naturally lend itself to nebulization. This approach also greatly facilitates the provision of multiple dose levels in early stage dose range finding trials because this can be achieved simply by varying volumes of a stock concentration delivered to the patients. Alternatively, this kind of flexibility can also be achieved via a capsule DPI with different fill volumes of a standard dry powder formulation, if this is more appropriate.
The third overriding consideration is whether the drug must be delivered to specific areas of the lungs. In these cases, smart nebulization may well prove to be the obvious choice for the early stages, as this offers the added benefit of providing patient feedback whilst maximizing lung deposition, especially to the smaller airways.
Reduced risk and savings in both time and money can all be achieved if phase-appropriate platforms are selected throughout the development process. Right up to the proof-of-concept stage, it is feasible to change the platform that is used, allowing for speed and value creation in the early stages before a more commercially-appropriate device is selected for later-stage trials.
This concept is now commonplace: the overriding desire is to get a drug into the clinic as fast as possible with a platform that allows dosing flexibility and maximizes deposition, and then focus on the ultimate commercial platform once the concept has been proved. As a result, smart nebulization and commodity capsule DPIs are increasingly being chosen for early stage clinical trials, allowing milestones to be achieved more rapidly. Whilst this initial choice may well remain suitable all the way to market, it might be deemed more commercially-appropriate to transition into a multi-unit-dose DPI instead, particularly if the application is very high volume and where moderate lung deposition may suffice, but also in instances where a multi-unit dose device is considered the standard of care, such as in the case of mild to moderate asthma.
The Covid-19 pandemic has highlighted the need for speed in the early stages of clinical trials. As the coronavirus can cause significant lung damage, there is a desperate need for inhaled therapies that can deliver drugs effectively to the lungs. Many therapies are being trialed, and speed is of the essence, therefore selecting the most appropriate device to allow projects to move into the clinic as soon as possible will allow successful treatments to be more quickly available for those patients who need them.
For early Covid-19 trials, it is likely that high drug deposition will be required in the small airways within the lungs, and it may be that delivering drugs using smart nebulizer technology will provide the best solution to prove the concept. With smart nebulizer devices, there is also reduced potential for there to be fugitive aerosol escaping into the environment because this can be an issue for conventional continuously producing nebulizer systems.
Alternatively, DPI platforms, especially off-the-shelf capsule devices, can also give a rapid route into the clinic if the drug is compatible with this approach. DPIs may have particular value for Covid applications where the drug is being given as prophylaxis or where medicine needs to be stockpiled against future pandemic outbreaks because of the high volume, low cost, generally long shelf-life and ease of use.
Regardless of whether it is a Covid application or not, all of the factors listed above should be considered when determining the best technology and the optimal device at each point on the development pathway. A methodical approach should be taken to analyze the advantages and potential drawbacks of all the options, narrowing down the choices based on the molecule’s properties, the technical requirements, any demands for speed and cost, and with a clear focus on the intended patient population.
Using phase-appropriate technologies may lead to a smart nebulizer or simple capsule device being chosen at the outset, allowing clinical trials to be initiated and proceed in a timely fashion but preserving the flexibility to then either stick with this platform for the remainder of the development or move to a different, more commercially relevant alternative for commercial launch.
Dr. Munro is responsible for Vectura’s new technology development and also for product development programs utilizing Vectura’s smart nebulizer devices. He joined Vectura in 2008 after a 20-year career at GSK, where he progressed to being Global Director of Inhaled Science and Technology. He holds a chemistry degree from the University of Edinburgh, and a PhD in synthetic organic chemistry from the University of East Anglia. He is also an honorary life member of the Aerosol Society.