By: Sara Sefton - Technical Manager - Pharmaceutical Development - Vectura
The use of dry powder formulations for administering drugs to the lungs has long been a strategy for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disorder (COPD). Delivering the active drug via a dry powder inhaler (DPI) allows patients to breathe the medicine directly into the lungs quickly, allowing rapid, systemic delivery of the drug to the bloodstream. This affords lower doses, eliminates the risk of first-pass metabolism, and greatly reduces the chance and severity of potential side effects.
From a manufacturing point of view, DPIs do not require use of expensive propellants, and can be relatively simple devices, reducing production costs. For patients, efficacy and compliance of use is generally higher than for nebulizers or pressurized metered dose inhalers (pMDIs), because DPIs are not reliant on patient coordination to deliver the drug. As such, delivering new drugs – as well as generic alternatives to existing drugs – using DPIs is an attractive option for drug development companies.
That being said, the development and manufacture of DPI products is complex, and requires coordinated, integrated strategies between formulation, device development, analytical and manufacturing teams, to ensure product efficacy, and overcome regulatory challenges. One crucial area to avoid setbacks and delays in development is ensuring that analytical methods are aligned with both the needs of the molecule, and the expectations of the regulatory authorities.
Characterization Methods Used in DPI Development
Most dry powder formulations are a blend of the micronized drug substance combined with lactose monohydrate and other excipients. For drug substances which are physically or chemically degraded by micronization, spray drying is an alternative method to produce the desired particle size for formulation.
Standard inhalation pharmacopoeia methods have their benefits, in as much as they can identify batch-to-batch differences and changes on stability of the aerosolized product and are simple and easy to use; however, in vitro/in vivo correlation can be difficult to achieve and their use in product development ultimately limited.
The particle size distribution of the drug substance, lactose, and the final formulation, are important parameters to measure and control to ensure consistency of blended product performance.
For spray-dried powders, techniques such as modulated differential scanning calorimetry (mDSC) and dynamic vapor absorption (DVS) give information on the amount and stability of the amorphous content, moisture uptake and sensitivity, and the nature of any phase transitions occurring, which can be used to modify manufacturing conditions to ensure a more stable formulation, providing a rapid screen of formulations without the need for extensive stability testing.
Use of advanced characterization tests can help to understand the aerodynamic particle size distribution (APSD) of the drug using moreanatomically relevant mouth/throat models coupled with actual or simulated breathing profiles, and affords further insight into how drug deposition actually occurs in the lungs. Furthermore, the fate of the aerosolized formulation at the local site of action can be better understood by assessment of its structural composition (degree of aggregation of drug/excipient particles) and the dissolution of the drug. This can be carried out using morphology directed Raman spectrometry (MDRS) and United States Pharmacopeia dissolution apparatus to analyze the aerosolized formulation.
An understanding of the deposition of the carrier in the formulation (e.g., lactose) can also provide useful information – but because lactose does not have a chromophore, traditional methods such as liquid chromatography with an ultraviolet detector cannot be used, so non-specific detectors such as charged aerosol detectors can be utilized instead.
The information from these tests can be used to further refine the manufacturing process parameters, the particle size distribution of lactose in the formulation, the particle size of the drug or the design of the DPI device.
Performing these tests at an early stage of the development process helps to target the formulation, reducing the need for multiple screening studies, and gives greater confidence in achieving the desired in vivo effects in subsequent clinical studies.
Challenges for Large Molecules
Developing DPIs using large molecule APIs brings a further set of challenges, because of the complexity of the molecules. Whereas the degradation of small molecules can generally be detected using a single method, such as reverse-phase liquid chromatography, large molecules have multiple mechanisms for degradation, including aggregation, oxidation, deamidation, hydrolysis, photolysis and other post-translational modifications. This means that a more orthogonal approach is required to evaluate the integrity of the molecule, and assessment of potential degradation mechanisms for each molecule will inform the critical quality attributes (CQAs), which in turn, will drive the selection of appropriate analytical methods.
Methodologies such as molecular weight determination, charge variant analysis, peptide mapping and plate-based assays such as potency, can all be employed to evaluate the degradation of large molecules in a formulation. Methods based on electrophoresis that allow protein separation by mass such as SDS-PAGE, and size-exclusion chromatography (SEC) can determine molecular weight, as well as detect the presence of degradants and higher-order species, while isoelectric focusing by gel or capillary electrophoresis can detect charge variants. Dynamic light scattering (DLS), which measures the size of the biologic, and Fourier transform infrared spectroscopy (FT-IR), which assesses the degree of unfolding/denaturation, can also be employed to determine whether any damage through the manufacturing process (for example during spray drying) has had an adverse effect on the integrity of the biologic API.
Additional consideration should also be given to the aerosolized powder, where a stability-indicating method is required for the assessment of emitted dose uniformity. In this instance, selection of a method that is sensitive to degradation through mechanical processes should be used. If the device chosen is a multi-use device, further consideration of the integrity of any residual formulation retained within the internal cavities of the device should also be evaluated.
Generic Product Development Using Advanced Analytics
In generic product development, it is necessary to compare the new drug product against a reference. Use of advanced characterization tests that have greater clinical relevance can help advance development by better characterizing and understanding both the test and reference product before embarking on costly pharmacokinetic (PK) studies. 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 utilized to characterize the powder within the reference DPI. Where a successful PK match is required between test and reference in terms of proving equivalence, use of more advanced characterization tests that offer greater clinical relevance are becoming more widely used. The results from these tests can be crucial in providing data that help drive product development before embarking on costly PK studies.
Draft product specific guidance documents for beclomethasone nasal spray and mometasone furoate pMDI have recently been published by the FDA’s Office of Generic Drugs, citing the use of alternative in vitro tests to be used in the place of a clinical end-point study. For the nasal spray, the use of MDRS to characterize the particle size distribution of the drug without influence from the excipient particles is cited. For the pMDI, the guidance document provides example alternative bioequivalence methods that could be used, including APSD testing using representative mouth-throat models (see Figure 1) and breathing profiles; characterization of emitted aerosol sprays with respect to velocity profiles and evaporation rates and dissolution and morphology imaging comparisons, including characterization of the full range of residual drug particle sizes.
Although there are currently product specific guidance documents that exist for DPIs, this accepted alternative regulatory approval route for a nasal spray and pMDI sets a precedent and demonstrates the potential for the approach to be accepted for a DPI.
Future Advancements in Analytical Techniques
Additional analytical techniques to support development programs have many benefits and, at Vectura, this has directly impacted the direction of numerous projects. In one program - a formulation development DoE of a generic DPI - predictive APSD testing using a representative mouth-throat model demonstrated a better match to the reference than standard compendial next-generation impactor (NGI) testing, and use of dissolution testing of the aerosolized products showed differences between formulations that were not observed with standard tests. This allowed development to be accelerated and refined to create a superior outcome.
European and US regulatory authorities are supportive of the efforts of innovators to increase generic competition within inhaled medicines, and reduce the time and cost of development. With safety and efficacy of products being paramount, it is clear that advanced analytical techniques that can fully characterize a product will become important, and so greater use of these methods, and full understanding of their potential will be needed. The benefits of utilizing advanced analytics in terms of time and cost savings mean that developers of DPI products should not be constrained by the standard pharmacopoeial tests. It is anticipated that other novel techniques will become more readily available to further add to the suite of characterization methods.
About the Author
Sara Sefton is Technical Manager at Vectura Ltd. Sara has over 20 years of experience in the pharmaceutical industry, ranging from drug discovery and product development through to commercial product support. Sara specializes in the development of analytical methods
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