A green light for cGMP aseptic spray drying

Aseptic spray drying was given a regulatory ‘green light’ with the FDA's approval of Raplixa. Dr Sam de Costa, Programme Manager, Nova Laboratories, believes the US decision is a boost for biopharma and future experimental medicines in parenterals or injectables

For two decades Nova Laboratories has provided clinical trials medication to a global customer base of pharmaceutical and biotechnology companies, academic and charitable institutions and the UK’s NHS. In this time the company has developed extensive expertise in the use of high-integrity, gassed isolator technology, which has been acknowledged by various regulators as ‘Advanced Aseptic Technology’. This expertise in complex and novel aseptic processes, clinical manufacturing of parenterals and devices now provides the company’s main role and has allowed it to develop commercial manufacturing processes for specialist sterile products.

However, it was the news that the US FDA had approved the Raplixa fibrin sealant and spray device that gave the most vivid green light to companies considering and exploring aseptic spray drying (ASD) as a manufacturing option. The FDA verdict marked a milestone for ASD in many ways, and was a significant regulatory milestone. Considering the technology has been available for some years without really achieving mainstream status, it probably takes the FDA decision to make the real difference.

The increase in enquiries that Nova has received since the decision suggests that the biopharma community is treating the FDA verdict as a vote of confidence in this enabling stabilisation technology. It has created the tipping point needed for those seeking a viable alternative to established processing methods such as lyophilisation.

Unlike low bioburden spray drying, aseptic spray drying does not need a terminal sterilisation stage during the manufacturing process

In part, it has been noticed that Nova is now manufacturing commercial supplies of Raplixa – an industry first in its own terms. But what has captured most attention is that Raplixa provides a classic illustration of an innovative drug presentation success where ASD has been instrumental in its development and in securing the licence. In fact, the real breakthrough is that Nova has managed the world’s first aseptically spray dried biologic, which should tackle the common misconception that thermo-sensitive biopharmaceuticals cannot be spray dried successfully. The newly licensed product can be stored at room temperature, illustrating a critical advantage of the technology.

Unlike low bioburden spray drying, aseptic spray drying does not need a terminal sterilisation stage during the manufacturing process because each step in ASD is conducted aseptically. This takes away possible in-process losses during manufacture and creates ready-to-use, room temperature-stable powders.

One of the primary benefits of ASD with respect to handling thermo-sensitive products is that even though relatively high drying temperatures can be used for processing, the pharmaceutical product is not fully exposed to it. During processing, droplets of formulation solution sprayed into a hot gas stream experience extreme evaporative cooling, which prevents the product from being heated to high temperatures. The surprisingly gentle processing conditions, combined with the short resident time of a dried particle within the drying chamber, minimises the probability of thermo-degradation during processing (see Figure 1).

Figure 1: The aseptic spray drying process
The spray dryer is located within a Grade A manufacturing environment and aseptically prepared liquid formulation is introduced into a sterile spray dryer via a spray nozzle.
The atomised liquid comes into contact with warm nitrogen drying gas and rapidly dries into powder within the drying chamber.
The drying gas carries the dried particles into a cyclone separator for collection.
Exhaust nitrogen is filtered and released as outlet gas.
Sterilisation of the spray dryer is carried out using a Sterilisation-In-Place (SIP) system.
The spray dryer is equipped with a Clean-in-Place (CIP) system for cleaning purposes.

This is in marked contrast to lyophilisation, which involves initially freezing liquid, then sublimating the ice into water vapour, and finally drawing off the water vapour. This puts products through extremes of temperature, which can lead to damage of active ingredients.

There are countless reasons why the industry is re-examining the potential roles and applications for ASD. One is that it simply opens up a realm of possibilities in fields like parenterals or injectables and in processing fragile and susceptible products such as antibodies, vaccines, live vectors and biologics. Another is the sheer range of pharmaceutical presentations and delivery methods that ASD facilitates through its flexibility. But the main reason may simply be that when it comes to manufacturing innovative drugs using novel delivery systems, it may be the only process capable of doing the job.

Enabling stabilisation technology

For those who recognise the importance of starting with the end solution in mind, one of the great advantages of ASD is that it can be used as an enabling stabilising technology in proof-of-concept feasibility studies and clinical trials and then taken to commercial scale production, as happened with Raplixa: a one-stop approach with huge efficiencies.

The FDA approval will make ASD a real option for those organisations exploring new drug candidates that need truly aseptic processing to open up drug delivery options for injectable-grade products, and Nova’s work with a range of biologics, from monoclonal antibodies to live-biologics products, shows just what is possible. It will make it a real option too where it is necessary to co-spray dry materials under different processing conditions and bring more efficiency to the manufacture of complex and novel presentations.

The advantage of ASD technology is that it can produce amorphous solid dispersions, and can significantly boost bioavailability even with less soluble molecules

In fact, ASD will become a more compelling platform for any investigational medicinal products. Its gentler processing conditions give more scope for particle engineering to develop and test unique particle characteristics and thus create innovative drug presentations. Through proof-of-concept spray drying trials with lab-scale spray dryers Nova can assess full product characterisation and powder filling options at a very early stage of drug development.

One of the main challenges for those developing new drug formulations is the need for greater bioavailability. The advantage of ASD technology is that it can produce amorphous solid dispersions, and can significantly boost bioavailability even with less soluble molecules.

With the massive potential for particle engineering offered within the ASD technology, it opens up real possibilities in sectors such as field and emergency medicines. To take one example, Nova has managed to create molecules that would ordinarily take up to 20 minutes to fully dissolve in liquid, and has achieved a dissolution rate of two minutes.

Of course, this extends to vaccines where advancements in bioprocess engineering have created increasingly effective formulations, where spray-dried molecules can be reconstituted at the point of administration and where even traditionally highly unstable products can be stored for long periods in non-liquid form, without refrigeration.

Expansion plans

Increasingly, companies developing new drug candidates through ASD are treating Nova as a one-stop facility from laboratory to commercial scale production. This approach minimises regulatory delays, allows the benefits of particle engineering to be explored early in the product lifecycle, cuts process development costs down the line, lowers the regulatory costs and those of spray drying, bulk powder blending and fill and finishing. It also enables early evaluation of the final product presentation and delivery options.

Having developed the world’s first cGMP aseptic spray dryer in 2008, Nova is now constructing a new commercial spray drying facility to come on line in 2017 and will offer a full service from discovery and development through to commercial supply. This will include a dedicated commercial scale in-house fill and finish operation, making it the world’s first commercial scale facility of its kind, creating partnership opportunities from feasibility study to commercial manufacture handling up to 5kg/h spray dried powder output.

Aseptic spray drying within a sterile environment

Innovation and sterility assurance are paramount issues. The company’s ability to design, construct and develop its own cleanrooms, isolator and process equipment also enables it to be innovative. Careful attention is paid to the design of the isolator systems to provide high sterility assurance levels through numerous contamination control design features which give complete barrier containment supplied within a Grade-A environment. During qualification, sterilisation cycles are performed to demonstrate the correct generation of the gas and the ability to achieve an environmental sterility assurance level of >106 throughout the isolator.

This provides an unparalleled sterility assurance and Nova has produced more than 1.5 million product-simulated media filled units with zero contaminated units from routine processes.

Companies