Time to powder your dose?

Aseptic spray drying is becoming widely adopted in pharma and biotech – but scaling up this approach to manufacturing can be difficult. Dr Sam de Costa shares his insights and considerations for a smooth transition

Simply put, aseptic spray drying is a process by which a liquid product is introduced to hot gas creating a dry powder, which is of injectable grade, under wholly aseptic conditions.

Aseptic spray drying has been available to the pharmaceutical industry for several years, but it has not yet achieved ‘mainstream’ status, and very few facilities are capable of commercial-scale output

Compared to traditional pharmaceutical spray drying – which occurs under cleanroom conditions – aseptic spray drying does not require a terminal sterilisation step. It is best compared to the process of lyophilisation – or freeze drying – in that both achieve a dried pharmaceutical powder from a liquid. However, the comparison must not go too far because of lyophilisation’s limitations or, to put it another way, aseptic spray drying’s many other enabling factors. It’s important to evaluate drying techniques early on to determine what impact that will have on product formulation. Aseptic spray drying has been available to the pharmaceutical industry for several years, but it has not yet achieved ‘mainstream’ status, and very few facilities are capable of commercial-scale output. Yet, since the FDA’s approval of Raplixa, the world’s first spray dried biologic, it is being increasingly adopted by pharma and biotech companies.

Due to the delicate nature of both biopharmaceutical products and the final processed powders, laboratory conditions must be carefully tuned to avoid the product’s quality and safety being compromised. As a basic requirement, any laboratory must adhere to Good Laboratory Practice, but further adaptations must be made to allow for optimal product quality. Spray dried powders, although variable in moisture content, are generally highly hygroscopic and will easily draw moisture from the surrounding environment. Therefore, a dedicated spray dried powder handling area must be established where the humidity is controlled, typically to less than 5% RH. Highly labile live biological products or proteins are sensitive to temperature which can rapidly lead to degradation. Therefore it is essential to maintain the feedstock during the entire spray drying process. In our development laboratories we routinely use temperature-controlled, product dedicated holding vessels during spray drying.

[caption id="attachment_58350" align="alignnone" width="620"] A specially prepared section is required to prevent contamination of the powders when they are created.[/caption]

Another consideration would be the type of drying and atomisation gas used for spray drying. For current Good Manufacturing Practice (cGMP) aseptic spray drying, pharmaceutical-grade nitrogen is used to prevent possible product degradation through oxidation. Therefore it is advisable to adopt similar measures within the lab. Similarly, nitrogen can be used during spray dried powder filling to overlay powder within storage containers, in-line with cGMP procedures. Use of pre-sterilised or low bioburden product contact parts can reduce the risk of cross-contamination. Adhering to the manufacturing practises during development can cut down inconsistencies of product quality between the laboratory and manufacturing-grade material.

In some instances, clients who have decided to undertake feasibility studies into aseptic processing may not have finalised the product specification. In our experience, if parameters are defined early on they can be implemented for the trials carried out in the laboratory, avoiding delays to the product development pathway. Therefore, a close collaboration between client and CRO/CMO is essential from laboratory stage. Selection of a suitable laboratory-scale spray dryer for early studies that can produce spray dried powder with similar characteristics to a larger scale manufacturing unit is an advantage. A laboratory with analytical capability to characterise spray dried powder, residual moisture content, particle size distribution, bulk density, morphology and compressibility will aid understanding of the product and smooth progression of the development phase.

One of the chief variables in the spray drying process is the control of particle size to meet a desired specification. Depending on the product’s applications, particle size can be the most important consideration in the early stages of development. For example, if the product is intended for emergency or field medicine, particle engineering can be carried out to cut dissolution rates. This increased solubility effect can be amplified even further by adding ingredients during the spray drying process. At Nova, we have been working on a major project to cut dissolution times for dried powder by adding what we term ‘blowing agents’ to the spray drying formulation. These agents enable the creation of hollow spheres with a greater surface area than those achieved under normal processing conditions, helping them to dissolve more quickly in liquid. Variables such as the type of nozzle selected will affect the size of particles, and the effect of this particular variable can be simulated in the laboratory, before the product is manufactured under aseptic conditions using larger-scale equipment.

Presentations such as vials, pouches, syringes and medical devices are all compatible with aseptic spray drying, and can be filled aseptically within the same manufacturing facility to reduce costs

Most clients, although they may not know the exact specification of their final product, will be aware of the commercial advantages they will gain if a certain product presentation is used. It is vital that desired presentations are shared with the CMO at feasibility stage so bespoke processing setups can be established, and product characteristics tailored accordingly. One of our major current projects is the production of a haemostat product applied directly to a wound in powder form. Two separate spray dried coagulation factors are mixed in the final preparation. Presenting the two components in a dry format allows our client to market this as unique product. Presentations such as vials, pouches, syringes and medical devices are all compatible with aseptic spray drying, and can be filled aseptically within the same manufacturing facility to reduce costs. If the product is intended for parenteral use, it is first necessary to look at the compatibility of the product with aseptic processing. For example, the filterability of a product must be evaluated at early stage within the laboratory as this can be a critical factor for processing.

From feasibility stage onwards, the process is fully scaleable to the point that we will soon be able to offer commercial-scale manufacturing at a new purpose-built facility. At feasibility stage, a liquid input of 0.5 kg/h per hour can be supported, at clinical supply stage, 3 kg/h, and at commercial manufacture stage, 20 kg/h. We are developing a commercial-scale manufacturing facility, in response to overwhelming demand from clients currently at later-stage clinical supply for a facility which can take the product to the next level. We expect this adoption of aseptic spray drying by the global pharmaceutical industry to increase substantially. When it comes to manufacturing innovative drugs using novel delivery systems, it is likely to be not only the most effective; it may be the only process capable of doing the job.

Too often, analysis and evaluation are seen as what happens after development as opposed to throughout the developmental process

It is most accurate to view aseptic spray drying as a facilitator for entirely unique particle characteristics and, therefore, novel and innovative drug presentations, including vaccines. Too often, analysis and evaluation are seen as what happens after development as opposed to throughout the developmental process. In an industry as regulated as ours, it makes sense to critically analyse and evaluate products at every step of development, to spot potential problems for things like delivery platforms and distribution methods early on.

Considering commercial manufacturing and distribution challenges at early development stages will make it easier to keep to budget and time restraints further down the line as well as proving early on that the product works at scale. Of course, this approach does require investment, but a good manufacturer should be able to offer you a cost and time-effective way of working without compromising on the final outcome.

Not everyone can take a product from the lab and scale it up to commercial manufacturing so it’s important you find a company that has the set-up and capability to see your project through to the end. Not only that, you need a manufacturer who has the regulatory approval process constantly in the back of their mind when deciding on process and formulation. This way they can be making representative material early on without the need for future bridging studies, which can add time and money onto any project. The earlier you think about delivery and formulation, the more likely it is that your product can make it out of the lab and into the hands of patients.

Author: Dr Sam de Costa is Stabilisation Projects Manager at Nova Laboratories Limited. Sam has considerable experience in sugar-glass stabilization of pharmaceuticals and holds a PhD in Biochemistry.