Speeding the drug delivery process

Drug delivery systems play a crucial part in differentiating a company's product on the market. Ensuring they work well can help speed up the route to commercialisation

Competition between pharmaceutical companies to discover and market successful medications is becoming ever more fierce.As a result, there is increasing pressure to look for ways to improve and differentiate their products, speeding the path from drug discovery to successful launch.

For pulmonary and nasal formulations, the interface between the drug and its specific delivery device can present a critical stage in this path.

By including the development of the drug delivery device at the earliest possible stage, pharmaceutical companies can improve competitive advantage and achieve a valuable reduction in time-to-market.

path speed

Accelerated Feasibility Testing (AFT) from Bespak's laboratories at the company's site in Milton Keynes aims to speed the path from drug discovery to drug delivery by combining formulation and container closure system (CCS) expertise at the beginning of product development.

The development of a delivery mechanism can consume a disproportionate amount of time and internal resource. By using AFT the customer can be given a quick assessment of whether their drug or formulation would be appropriate for dispensing via a pressurised metered dose inhaler (pMDI) or a nasal delivery system. 'The benefit of the AFT service is that it can be offered in modules' said Dr Tol Purewal, head of r&d at Bespak.

'Pharmaceutical developers can use this service at practically any stage of development to optimise the container closure system for their specified formulation, or to test performance characteristics with some of the most advanced equipment available. This has the potential to optimise development time.'

To characterise the pharmaceutical and physical performance of pMDI systems, Bespak has made ongoing investment in trained staff and the necessary scientific equipment. Laboratory scale filling equipment enables the company to manufacture drug formulations in combination with a range of can, valve and actuator variants.

manufacturing process

There are two main pMDI manufacturing processes: cold filling and pressure filling. Cold filling involves cooling the formulation excipients to -50⁰C thereby keeping the propellant in a liquefied state. The formulation is then metered into a container and the valve crimped on.

There are two pressure filling techniques, figure 1 - single stage and two stage. In single stage pressure filling technique, the formulation excipients are added to a pressurised batch vessel. The empty can is then purged using a small amount of propellant to expel air, the valve is crimped on and the formulation metered into the can through the valve.

Two stage pressure filling involves preparing a product concentrate containing all the formulation excipients apart from the propellant. The product concentrate is metered into the can, the valve is crimped on and the propellant is then filled into the can through the valve.

Once samples are manufactured, Bespak performs physical and pharmaceutical performance tests to characterise the complete pharmaceutical product.

Physical performance testing uses laser-based systems and analytical testing techniques, such as Malvern's Spraytec, to provide accurate analysis of the pharmaceutical product performance.

Such systems enable the particle size distribution of an aerosolised spray to be measured by laser diffraction, figure 2. A laser beam is passed through the aerosol cloud produced by the pMDI and is 'scattered' by the particles or droplets before being collected on a series of sensors arranged in concentric rings. The scattering pattern is then used to calculate the size distribution within the spray. Key parameters determined from the scattering data collected are the median droplet size, upper and lower tenth percentiles and the total amount of light transmitted. These are used to characterise the spray, although other size descriptors are also available. The measurement returns time-dependent information and enables characterisation of the initiation phase, the stable phase and the breakdown phase of a spray.

Spray characterisation is further enhanced by the use of a high speed video (HSV) system in combination with a thin layer pulsed laser sheet to measure the geometry of the emitted spray plume. The HSV frame rate of up to 955 frames per second is synchronised with the pulsed laser to produce an image of the spray with dramatically reduced 'motion blur'. Plume geometry is measured using a single image from the stable phase of the spray and involves measuring the angle, height and width of the spray, figure 3. For spray pattern analysis, figure 4, the frames captured are electronically merged into a single image which is representative of the entire spray. From this composite image the spray centre and longest diameter are

determined.

spray patterns

This technique also enables the evaluation of time-based elements of spray performance and shape. These tests are requirements in an FDA's draft guidance.1 Additionally, spray pattern and plume geometry are required in pMDI product data packages for the FDA.2 Other performance tests are performed to characterise the product, the main ones being leakage rate, visual appearance and valve force characterisation.

In addition to physical performance tests there are a number of pharmaceutical performance techniques routinely used to evaluate the pharmaceutical product. Standard tests include:

• total can content;

• through life dose content uniformity;

• particle size distribution by Andersen Cascade Impaction;

• degradation/impurities testing; and

• moisture content.

Additional tests can be performed to further characterise the product or to address specific performance characteristics. These include loss of prime and loss of dose testing as well as in-use patient simulation studies.

particles collide

The underpinning analysis technology for these measurements is High Per-formance Liquid Chromatography (HPLC), except moisture testing, which is performed using Karl Fischer moisture determination apparatus.

The Andersen Cascade Impactor (ACI) is designed to characterise the aerodynamic particle size distribution of the sprayed dose and is a testing requirement of the United States Pharmacopoeia (USP), figure 5.

Within the ACI the aerosol passes through a series of stages that have nozzles of decreasing diameter. Between each stage, there is a collection plate so that particles with the largest aerodynamic diameter will impact on the first collection plate and smaller particles will follow the air streams to a collection plate at a subsequent stage dependent on their size. In most cases stages 3 and 4 (collecting particles of 2.1-4.7mm) are of interest for the delivery of respiratory medicines as these represent the trachea and primary and secondary bronchi in the human lung.

The final stages of the ACI collect particles of less than 1.1mm and so are more important to those considering delivery for systemic treatment to the highly vascularised alveoli. The final stage is an absolute collection filter so that only the very smallest particles (e.g. below 0.47mm) will deposit on this plate. The drug content present on each filter is assayed and the calculated aerodynamic diameter known as the Mass Median Aerodynamic Diameter (MMAD) is derived from the results. The Respirable Fraction (the ratio of the respirable dose to the ex-actuator dose) is also calculated from ACI results.

Through-life dose content uniformity testing assesses whether the product will deliver the required dose throughout the life of the pMDI.

The pMDI unit is fired into a collection tube and the sample collected is then assayed, figure 6. Typically this test is performed at the start, middle and end of unit life.

An AFT project is typically undertaken in four key stages. Initially, Bespak reports on the feasibility of delivering the drug and formulation based on the customer information supplied. At the next stage, physicochemical formulation studies are conducted in parallel with CCS compatibility studies, to establish the formulation characteristics and interactions with the CCS.

The formulation is then analysed along with the CCS options to identify the most suitable system in terms of pharmaceutical and physical performance. Physical testing includes a quantifiable assessment of leakage rate and shot weight through the product's life, as well as visual appearance analysis.

drugs tested

Pharmaceutical performance assessment includes the level of drug degradation and impurities, through life dose content uniformity, loss of dose, particle size distribution, drug content assay and moisture content. Finally, the product is tested in a short term stability study under accelerated conditions to evaluate both physical and pharmaceutical performance. This provides evidence of any variations in product quality under the influence of temperature, humidity and time. The resulting technical recommendations are supported by a complete data package.

All these tests are used for pulmonary products. The HSV and the Malvern Spraytec are also used to characterise the performance of nasal products. Bespak is also developing advanced nasal product characterisation techniques, including casts developed from human nasal scans. These are used to evaluate spray deposition in the nasal cavity and to develop nasal delivery devices with enhanced performance.

Dr Purewal said: 'Our expertise is in understanding the drug-device interface. We keep our partners fully informed of how the formulation is progressing with the various delivery systems we can offer. With success at every stage, the process can be completed in a few months, freeing resource within the pharmaceutical company development team that can be applied to other projects.'