Pressurized Metered Dose Inhalers (pMDIs) are complex systems and understood to be technically challenging to develop. In order to successfully formulate a pMDI system, there are many factors that need to be assessed and brought together. The formulator must ensure that the finished product is safe and efficacious for the duration of its shelf life.
A pMDI system is made up of a number of sub-systems, all of which are required to operate with one another to ensure that the finished pMDI product works correctly. To broadly summarize, these sub-systems include the formulation, container closure system, actuator and secondary packaging (Figure 1). The development of pMDIs requires a total system approach to fully design and optimize the production in order for it to meet its stated design requirements.
During critical early-stage development, formulation options are assessed and developed based on a defined, scientific approach. The aim is to repeatedly demonstrate, with meaningful analytical methods, that the formulation is capable of meeting the required product performance criteria. In light of the range of components within a pMDI system that can, and should be optimized and understood (see sidebar, page 14), the following offers an overview of some of the generic activities required to perform early phase formulation and optimization of a robust pharmaceutical pMDI system.
Project Preparation and Scoping: During this initial stage, all supplied and public domain information is reviewed. An assessment of project risks is also initiated. This should ensure that all prioritized factors are included in the work plan.
In scoping a project, it is vital that all factors within the plan are considered, even if only a subset may require further investigation. A record of this decision should be kept to help inform any future investigation requirements.
Pre-Formulation: During this stage, the API should be characterized. This will involve understanding the key solid-state and physical properties that influence pMDIs. These factors may include polymorphic form, amorphous content, purity and hygroscopicity.
In the first instance, the above factors should be assessed thoroughly at the onset of the project and re-assessed at key times as the project progresses — for example, following particle engineering. Alternatively, specific studies could be performed to investigate the effect of different factors on the above.
Similarly, excipient characterization should be performed on potential excipient options, although it is generally assumed that data may be transferred between projects for common excipients. If a study is required, then tests similar to those performed during Active Pharmaceutical Ingredient (API) characterization should be investigated.
PARTICLE SIZE REDUCTION
Particle size reduction should be undertaken for systems that are likely to necessitate formulation as a suspension product. Note that engineering trials will not be required if a solution formulation route is indicated by an initial theoretical assessment of solubility or solubility study. The aim of a particle engineering study is to identify a suitable process and optimize critical controls for producing size-reduced material. Once a suitable method of particle size reduction has been identified theoretically, a study will typically be performed to establish an operating window and will be based on a Design of Experiment (DoE) type approach. The purpose of this initial study is to generate early data and to allow initial lots to be manufactured.
For the purpose of this article, let us assume that particle engineering is based on jet micronization or spray drying. If adopting a jet micronization process, experimental factors may include product feed rate, ring pressure and Vecturi pressure. If adopting a spray drying process, experimental factors may include product feed rate, aspirator speed and inlet temperature. In each case, parameters will be optimized for Particle Size Distribution (PSD) and yield.
An experimental design, based on a full-factorial design with center points may be utilized. Responses may include:
• PSD by laser diffraction
• Polymorph assessment
• Assessment of change from Input Raw Material (IRM)
The experimental output should identify a suitable process to produce particle size reduced material in the appropriate PSD. It may be desirable to take two or more options forward into further experimental testing; for example, to allow optimization of the Aerodynamic Particle Size Distribution (APSD) to be performed.
SOLUBILITY, GROSS CHEMICAL COMPATIBILITY
Pre-formulation activities will be completed by performing a study to determine the solubility of the API in potential HFA-based systems and to assess the potential for formulation of a suspension or solution-based system. Dependant on the API, it may also be necessary to assess the level of solubility in co-solvent only. Additionally, this study should provide an early indication of solubility-related effects for suspensions, such as Ostwald ripening. This assessment will typically include all propellant options (e.g., Propellant 134a and Propellant 227).