Fergus Manford is patent attorney, intellectual property, Vectura.

Fergus Manford

For inhaled products, dry-powder inhaler (DPI), pressurized metered-dose inhaler (pMDI), and nebulizer devices are the most commonly used delivery platforms, with others that have less common, niche applications. The choice of delivery platform may be driven by different factors at different points in the development cycle; one device may be used up to proof-of-concept and an alternative chosen for commercialization.

Each drug program has unique drivers; factors related to the device platform, in combination with the drug’s needs, should be evaluated for each new product concept and development program. A device-agnostic development approach is best to avoid being swayed by previous programs or a technology bias towards a single platform.

Considerations are both technical—the API and its associated physical properties and dosage requirements—and also practical—the target patients’ needs, such as age, usability, lifestyle, and expectations based on other available devices. Additionally, there are therapeutic target considerations and strategic and commercial ramifications of a program, depending on the innovators’ goals and lifecycle plans. Making informed choices at a given stage of development can save time and money while maximizing the probability of a project’s success.

The use of dry powder formulations originally focused on respiratory diseases such as asthma and chronic obstructive pulmonary disease. Pulmonary administration of an API provides direct, rapid action when treating these diseases, and a DPI allows patients to breathe medicine into their lungs quickly, while being breath-activated, meaning that the act of breathing through the inhaler releases the drug into the lungs. There are a variety of DPIs, some with a supply of the drug inside, and some where the drug needs to be added to the device before use.

Dry powder formulations delivered to the lungs offer numerous advantages. In the deep lung, the tissue wall is only one cell thick, allowing rapid, systemic delivery to the bloodstream. This approach affords lower doses, eliminates the risk of first-pass metabolism, and reduces the chance and severity of potential side effects. DPIs are generally small and portable, do not require use of expensive propellants, and can be relatively simple devices, which can result in lower manufacturing costs.

The development and manufacturing of DPI products is complex, and close integration between formulation, device development, analytical, and manufacturing teams can help overcome challenges and shorten timelines, reducing the risk of expensive and time-consuming changes later in development.

There are a number of DPI device options open to innovators, and selection is important both for the drug and the phase of development. For accelerated development to achieve clinical milestones, a capsule device may be appropriate. For commercial purposes, blister-based, multi-dose, commercially validated devices may be more suitable.

Choosing a DPI starts with the defined target product profile (TPP) and matching it to the user requirements. Ultimately, the device must deliver the required payload of drug to the desired site in the patient’s lungs; and the patient must be able to use the device easily.

DPIs are not generally used for pediatric purposes; patients who have arthritis, have low strength, or are unable to inhale at a sufficient flow rate could struggle to actuate the devices. Consideration also has to be given to populations who may be lactose intolerant, if that is selected as an excipient.

Leveraging an established platform technology allows previously verified and validated functional elements to be combined as needed to meet TPP requirements.

As with all device development, early human factors tests help in ensuring patients will use and interact with the device as intended, ensuring both patient compliance and effective delivery. Market intelligence and vigilance of similar products is necessary to understand likely problems in the commercial environment.

Bespoke DPIs offer advantages for potentially non-standard formulations and where intellectual property must be protected. This option, however, must factor in the device’s functional attributes and physical characteristics, as well as formulation needs, safety, reliability, and standards and regulations. Practical aspects of construction and use, including cleaning, maintenance, and lifespan must also be evaluated, and balanced against potential impact on the supply chain, prescriber, and payer.

Designers and innovators must ensure the compliance of the patient is still at the core of product design, but factors including cost of goods, safety, and effectiveness are crucial in the operational success of any device and creating solutions to real problems by designing the right medical device.

The combination of formulation and the device used to deliver it is integral to an effective drug product, and the key areas to consider when developing a DPI formulation are the drug substance, excipients, and the processing method.

Most dry powder formulations are a blend of a micronized drug substance with lactose monohydrate and other excipients. The forces of particle cohesion and adhesion in the dry powder formulation are key; to manipulate these to the optimal parameters, additives, excipients, or particle engineering measures are used. When designed properly, these factors enable the patient to successfully empty the dose receptacle and achieve reproducible dose delivery during inhalation. The drug product must also be uniform, a common challenge in carrier-based formulations.

Drug formulation stability is also crucial, both from a physical and chemical perspective. The API’s properties must be understood to evaluate the risk of particle-particle, moisture, and excipient interactions, and the appropriate processing method and excipient choice, as well as potentially incorporating moisture protection in the dose packaging, can be used to minimize stability issues. Biologics molecules are particularly prone to instability, as formulations with reducing sugars such as lactose can react with functional terminal amines of peptides or proteins.

A design-of-experiments approach is often used to understand the interactions between the drug’s characteristics, excipients, and processing conditions. For drug substances that are physically or chemically degraded by micronization, spray drying is an alternative.

Whatever device delivers the drug formulation, flowability of the powder is paramount, and excipient choice is a major factor in maximizing this. During development, consideration must be given to the filling technology, whether into blisters or reservoirs; drum filling, capsule filling, and fill-to-weight technologies are commonly used.

Spray-dried powders tend to be hygroscopic, so performance can be quickly compromised by moisture absorption, whereas this is less common for lactose blends. Preventing segregation is critical for reservoir devices to ensure consistent metering and dosing; however, for blister formats, segregation does not impact the dose unless it reaches a point where the powder cannot readily be aerosolized, and the dose evacuated is impacted.

For spray-dried powders, techniques such as modulated differential scanning calorimetry and dynamic vapor absorption give information on the amount and stability of the amorphous content, moisture uptake, sensitivity, and phase transitions. This analysis can be used to modify manufacturing conditions to ensure a more stable formulation and provide a rapid screen of formulations without the need for extensive stability testing.

The complexity of large-molecule drugs presents additional challenges to DPI development. Small molecules can undergo chemical degradation, and the degradation products can generally be detected by a single method such as reverse phase-high performance liquid chromatography. Large molecules have multiple degradation mechanisms, and so a more orthogonal approach is required to assess the molecule’s degradation. Assessment of potential degradation mechanisms for each molecule will inform the critical quality attributes (CQAs), which drive the selection of appropriate analytical methods.

For a generic drug DPI program development, where the test product must match the reference, experience in formulation development can significantly speed the development process. Testing is vital to understand aerodynamic particle size distribution of the drug using more anatomically relevant mouth/throat models coupled with actual or simulated breathing profiles, as well as getting further insight into where the drug deposits in the lungs. Morphology-directed Raman spectrometry and United States Pharmacopeia dissolution apparatus also gives insights into the fate of the aerosolized formulation at the local site of action by assessment of its structural composition and dissolution of the drug.

Deposition of the carrier in the formulation can also provide useful information, and experience in method development in similar models and instruments reduces method development time. This information can guide further refinement of manufacturing process parameters, the particle size distribution of lactose and the drug, or device design to enhance delivery. Performing these tests early on helps target formulation and reduces the need for multiple screening studies, giving greater confidence of clinical success.

Advanced analytical tests can be used to characterize the powder within the reference DPI, and where a successful pharmacokinetic (PK) match is required between test and reference, use of more advanced characterization tests that have greater clinical relevance can be a powerful tool to help drive product development before embarking on costly PK studies. European and US regulatory authorities are keen to see greater generic-drug competition and are supportive of efforts to reduce the time and cost of development, while maintaining product safety and efficacy. This generic-drug competition can only be achieved by greater use and understanding of these advanced analytical methods. While standard methods still have uses in formulation development, advanced methods are beneficial, and developers of DPIs should not be constrained by standard pharmacopoeial tests.

A key challenge in manufacturing inhaler devices is evaluating what constitutes an appropriate scale at each development stage. In early development, when materials are often in limited supply, there is an inevitable conflict and balance between the scale of manufacture and the number of batches needed to build scientific understanding.

Depending on whether a DPI device uses a capsule or a blister-
based platform for commercial purposes in early development, capsule-based technology is seen as preferable as it offers flexible dosing and a relatively quick pathway to clinical phases.

However, capsule development brings different considerations and complexities as dry powder blends can interact with the capsule material. Capsule composition (typically gelatin or hydroxypropyl methylcellulose), water content, lubricant level, and surface quality can result in changes in performance, chemical stability, physical sticking, and agglomeration. The characteristics of formulation and device must be understood so that the most appropriate capsule type can be matched. Effective control of manufacturing environmental conditions and long-term packaging considerations are necessary to maintain stability and performance of capsule-based DPIs.

Developing validated models in the early phases that establish robust processes can mitigate the risks associated with scale up. If comparable drug product performance from batches made at laboratory-scale and commercial-scale can be established, a significant amount of the development work can be conducted at a smaller scale, reducing material costs and enabling faster execution of experiments, while giving confidence in future scale up. It also allows capital investment in commercial manufacturing to be made on a risk-based approach, once milestones have been reached.

For these models to be effective, early-phase development equipment and processes should be synergistic with that at the scale-up phase, reducing the required data capture for critical process parameters (CPPs) and CQAs. Involving late-phase manufacturing teams early in development can reduce the risk of issues later in the product lifecycle. Using cross-functional teams and streamlined protocols to ensure all CQAs and CPPs are captured can simplify the process and reduce delays in later development.

Lean manufacturing techniques can ensure optimal resource and equipment utilization and future-proofing capacity can be done by sourcing equipment that is directly scalable from that used during early-phase development. Effective and timely sourcing of device components, as well as excipients and APIs for manufacturing campaigns, can mitigate against drug shortages. Forward-looking allocation of resource, as well as the ability to repurpose or procure additional equipment and resource with speed, is also key to maintain delivery supply chains.

From all the options open to developers of inhaled drugs, DPIs have many advantages, but the development and manufacturing of devices is complex, and respiratory formulations are a balance between formulation considerations, delivery device, and patient population.

Device and formulation development are symbiotic, and each must take into account the effects and interactions on the other, and overlooking issues of scalability at an early stage can avoid changes in later development phases, which can be especially time-consuming and costly. Using a development partner with experience in both device and drug development, and the regulatory and manufacturing needs for commercialization, allows program teams to integrate the formulation, device development, analytical, and manufacturing development to avoid potential challenges and shorten timelines.

Sara Sefton is technical manager, pharmaceutical development; Fergus Manford is patent attorney, intellectual property; Tim Gardner is director, manufacturing and NPI; and Andrew Walker is vice president, device development, all with Vectura.

When referring to this article, please cite it as S. Sefton, et.al., “Integrated Approach Facilitates Inhalation Drug Development,” 

Articles

The choice of delivery platform for inhaled drug products is contingent on API-related factors, as well as the development stage of the product. 