Achieving Aseptic Drying With Spray Drying Technologies

How is spray drying being used in the pharma industry?

Spray drying has played a significant role in the pharmaceutical industry for many years in the drying of excipients, APIs and final drug formulations. To a large extent, interest in spray drying has been fuelled by the fact that it is in an 'enabling technology'; for example, using spray drying to produce amorphous solid dispersions can improve the performance of poorly soluble APIs. Also, processes that are based on organic solvents are ideally suited for spray drying and produce results that generally surpass those of alternative technologies.

Interest has also spread to other areas where spray drying may be more economical or where the particle engineering possibilities are better than the traditional methods of production. Examples could be to obtain controlled release or to produce very fine powders for inhalation.

When designed for aseptic production, spray drying can be used to produce aseptic products, such as vaccines, antibiotics and other parenterals.

Spray drying is a simple process where droplets/particles are dried while suspended in a drying gas. This turns a liquid formulation into a dry powder in a single, continuous process. The basic spray drying process has three essential steps:

• Atomisation, where the droplets are formed.

• Drying gas and droplet contact, where the liquid is evaporated.

• Powder recovery, where the dried particles are separated from the drying gas stream.

The spray dryer is a suspended particle dryer. Drying particles while suspended requires drying to be very fast and droplet trajectories must also be kept away from the drying chamber wall for as long as possible

Fast drying is achieved by effective and uniform atomisation of the liquid, which creates a very large surface area and by ensuring effective mixing of the droplets with the drying gas

Because of the relatively short residence time (a function of the size of the drying chamber and the flow pattern of the drying gas), the process requires small droplets in order to work properly. The smaller the drying chamber, the smaller the maximum particle size that can be successfully dried. Hence, the spray drying process is most limited at the small scale, where as scale-up provides more opportunities and improved process robustness.

The fast drying, the short residence time and predictable temperature exposure—caused by the effective mixing of the droplets with the drying gas—results in a lenient drying process that can be adjusted for a range of process conditions, including the drying of heat sensitive materials such as live vaccines and complex proteins. Just as importantly, spray drying is a highly reproducible process that can be predictably scaled up to nearly any production size.

Spray drying also offers a range of particle engineering possibilities. By altering the process parameters (and/or spray dryer configuration), spray drying can produce complex particulates that meet exact powder properties in terms of particle size and shape, bulk density, dispersability, polymorphism, flow properties and so on. A good example is the manufacture of a polymer-stabilised, amorphous solid dispersion of an API for direct compression into tablets without an intermediate granulation or mixing stage. In this case, the process conditions are chosen to produce a homogenous, free-flowing and non-dusty powder of good density from a liquid formulation that contains the necessary components of the final tablet in solution or suspension. The fast drying at low temperatures (below the glass transition temperature) will intentionally favour the amorphous form of the API/polymer mixture. In other cases, the requirement may be completely different; for example powders for inhalation must have a small aerodynamic size, resulting from the small geometric size and low density.

In short, spray drying is a very versatile lenient drying process that turns a liquid into a powder in a single process step at any scale with particle engineering possibilities that makes the technology worth considering even when drying is not otherwise required. Spray dryers can be built for operation with a wide range of (flammable) solvents as well as water, for congealing of melts, for contained processing of potent compounds, for aseptic processing and for agglomeration with integrated fluid beds and more.

How do aseptic spray dryers differ from non-aseptic spray dryers?

Pharmaceutical production under aseptic conditions has to be a validated process that fulfills the requirements established by the relevant authorities, including requirements for how to sterilise the plant and for maintaining of sterility throughout the full production run. An aseptic spray dryer is differentiated from a non-aseptic one only in the requirements for sterilisation and can be used for the same processes, such as particle engineering, lenient drying, scalability and use of organic solvents, as a non-aseptic spray dryer.

The challenges of using spray drying in aseptic production mainly relate to three areas:

• plant sterilisation

• maintaining sterility during production

• product handling (e.g., filling of vials).

A fundamental difference between the use of a spray dryer compared with aseptic liquid and typically aseptic-lyophilised formulations is that it requires aseptic powder filling into vials as opposed to aseptic liquid filling. In the case of lyophilisation, vials must also be loaded prior to the drying process. However, aseptic powder filing is a well-established technology with several providers in the market.

To ensure that sterility is maintained during spray drying, all gas entering and leaving the sterile drying zone must be adequately filtered. The liquid formulation must also be adequately filtered. However, this may not always be possible, in which case sterility must be ensured through other means, such as preparing the formulation under aseptic conditions using sterile components.

What methods are used for sterilising spray dryers?

An accepted method for the sterilisation of spray dryers that meets the requirements from drug approval authorities is the key for wider use of spray drying in aseptic production. Traditionally, spray drying sterilisation methods have included:

• off-line sterilisation in a autoclave or sterilisation oven

• in-place sterilisation by dry heat

• in-place sterilisation by steam.

Off-line sterilisation is ideal for small plants that can be dismounted and assembled aseptically after sterilisation (e.g., inside an isolator). Small plants and the associated ductwork have a large surface area to volume ratio, which makes dry heat sterilisation problematic, and off-line sterilisation offers a less complex solution compared with in-place sterilisation by steam.

In-place sterilisation by dry heat takes advantages of the fact that a spray dryer is designed for hot gas. However, the high temperature requirements (typically 170 °C) and the limited heat capacity of air or nitrogen make it difficult to heat up the inside surface of plant and ductwork where cold bridges are present.

Sterilisation by steam has been the preferred method for sterilisation in the pharmaceutical industry for decades and is used extensively for lyophilisers. This method is also applicable for spray dryers if it is designed as a pressure vessel.

A novel sterilisation process for lyophilisers is H₂O₂, which is approved by both the FDA and the EMA. For spray dryers, H₂O₂ or other gases have not been used for sterilisation. Compared with the internal surfaces of a lyophiliser for vials, the internal surfaces of a spray dryer are direct product contact surfaces. H₂O₂ or similar gases have not been used because they have not yet found general acceptance as means for sterilising direct product contact surfaces.

Are there any difficulties associated with cleaninplace in preparing for aseptic spray drying

Clean-in-place (CIP) is a wellknown operation. As long as the CIP solutions do not impair the sterilisation of the spray dryer, they are no different from other high-performance CIP systems used for non-aseptic pharmaceutical spray drying.

A filter integrity test is performed at the beginning and end of each cycle to ensure that the filters are functioning as intended. Sterilisation is done by Steam-in-place (SIP) of the complete spray dryer, including feed line, nozzle and sterile filters. SIP is performed as an evacuation and heating sequence followed by a steam sterilisation sequence at a minimum 121 °C for 20 min. The evacuation and heating sequence consists of a series of evacuations separated by steam injections, which ensures the removal of air and heats the dryer prior to the sterilisation sequence itself. The removal of non-condensables and the heating sequence is important for the plant to be fully sterilised. Crucial parameters include not only the sequence of evacuation and steam injection, but also the duration of the steps and the pressure by which they are conducted.

How does aseptic spray drying compare with other aseptic technologies?

Liquid formulations are the preferred drug delivery solution for a wide range of sterile pharmaceuticals because they are well accepted with low-cost processes and offer relatively good convenience for the user. Product stability and cold chain challenges, however, make dry formulations attractive solutions as well.

Today, most dry formulations are produced by lyophilisation, which is a long-established process for producing stable powders, but has a high-total cost for installation and operation. It is also a lengthy batch process (often up to 48 h to process a batch) that carries the risk of losing a whole batch if, for any reason, process conditions are not maintained throughout the cycle. To reduce the risk of losing a batch, there should be backup systems in place, but this increases both installation and operation costs.

Compared with lyophilisation, spray drying is generally more flexible in terms of product and powder characteristics and processing time. However, the yields in spray drying processes are typically around 98–99% rather than 100%, which is the theoretical level that can be obtained in a lyophiliser (under the condition that all batches are successfully processed and that all vials come out in perfect shape). This can make a significant difference on expensive products. Additionally, because spray drying is very flexible in terms of product and powder characteristics, there are possibilities for making the wrong powder characteristics. In many cases, this is apparent only as poor yield. For small development batches produced on small laboratory or pilot spray dryers (frequently with non-optimised process conditions and equipment), the yield may be significantly less than what can be achieved on full batches and with optimised process conditions. This is important to keep in mind in order to avoid rejecting the spray drying technology due to wrong selection of process conditions or equipment.

Comparing the costs of the two technologies, spray drying is in general more economical in terms of installation and operation compared with lyophilisation. For instance, the evaporative capacity of a normal-sized pharmaceutical spray dryer can match that of 5–7 large lyophilisers. Full operational and life cycle costs must also be considered when comparing the two technologies.

In many cases, however, spray drying and lyophilisation are complementary technologies. For small batches of difficult-to-dry powders to be supplied in vials, lyophilisation has an advantage, whereas spray drying has an advantage if free-flowing powders are required, and for productions in large quantities.

Henrik Schwartzbach Senior Process Technologist at GEA Niro