Designing Grade A environments for drug development through to full manufacture


Pharmaceutical manufacturers are under increasing pressure to guarantee drug sterility. Simon Phillips, Head of Sterile Manufacturing, Nova Laboratories, explains how designing the right Grade A environment at a drug’s development stage can alleviate pressure further down the line

For two decades Nova Laboratories has provided clinical trial supplies to a global customer base. In this time the company has developed expertise in the use of high-integrity, gassed isolator technology which has been acknowledged by various regulators as ‘best practice’. The company’s work on complex and novel aseptic processes and clinical manufacturing of parenterals and devices has enabled it to develop commercial manufacturing processes for specialist sterile products that are to be marketed following successful clinical trials.

The company can design, construct and develop bespoke isolators, cleanrooms and associated process equipment for customers and boasts more than two million media fill simulations to date across a range of complex presentations with zero failure rate. This high level of sterility assurance is obtained by a combination of isolator design, use of highly trained staff, strict controls for the sterilisation of components, process design and the careful selection of suitable equipment for complex sterile processing.

To meet increasing regulatory pressures, customers are looking for help with the high levels of sterility assurance needed during product development, which can then be scaled up for commercial manufacturing further down the line. A recent example is the manufacture of Raplixa, by an aseptic spray drying process developed at Nova.

US Food and Drug Administration (FDA) approval of Raplixa in 2015 was a green light to companies considering aseptic spray drying as a manufacturing option

Spray drying is an established industrial process used for non-sterile manufacturing by the food and pharma industries. Nova has adopted this technology to manufacture injectable grade pharmaceutical drug product under cGMP, sterile conditions. The company’s isolators provide a blank canvas with which it designs bespoke sterile processes to meet client needs. An example of this is the development of aseptic spray drying for use as an enabling stabilising technology in proof-of-concept feasibility studies and clinical trials and then taken to commercial scale production. Nova’s experience of this route was through the drug product Raplixa – see Case Study 1.

US Food and Drug Administration (FDA) approval of Raplixa in 2015 was a green light to companies considering aseptic spray drying as a manufacturing option and was a significant milestone for aseptic spray drying for many reasons, including regulatory compliance. Subsequently, there has been plenty of interest from the biopharmaceutical community in aseptic spray drying. It has created the tipping point needed for those seeking a viable continuous production process as an alternative to established batch processing methods such as lyophilisation.

There are several reasons why industry is re-examining the potential roles and applications for aseptic spray drying

The development and commercialisation of the world’s first aseptically spray dried biologic should tackle the common misconception that thermo-sensitive biopharmaceuticals cannot be spray dried successfully. There are several reasons why industry is re-examining the potential roles and applications for aseptic spray drying. Its main advantage is that it enables stabilisation of susceptible products such as antibodies, vaccines, live vectors and biologics.

Having developed the world’s first cGMP aseptic spray dryer in 2008, Nova Laboratories is now constructing a new commercial spray drying facility to come on line in 2017. It will offer a full service from discovery and development through to commercial supply that will also include a dedicated commercial scale in-house fill and finish operation, creating partnership opportunities from feasibility study to capacity of up to 5k/hr output of spray dried product.

Case study 1 – Enabling an innovative drug presentation

In May 2015, the FDA approved Raplixa from ProFibrix. The approval was based on a large Phase III, multicentre clinical trial involving 721 patients in four countries in different surgical procedures. The Raplixa clinical supplies were manufactured by Nova at its sterile manufacturing facilities and comprised of spray dried thrombin and spray dried fibrinogen, which are blended and filled aseptically.

Small aseptic spray dryer

Small aseptic spray dryer

Nova had worked very closely with the customer over a five-year period, gradually upscaling from laboratory developmental scale to clinical trials production in its pilot spray drying facility, to obtaining regulatory approval for commercial manufacture.

The FDA approved the Raplixa fibrin sealant and the Raplixa spray device to provide adjunctive haemostasis for mild to moderate bleeding in adults in surgery. Raplixa needs no thawing, reconstitution or mixing and can be applied directly from the vial or with the device, a low-pressure spray applicator, to the bleeding site. Here it dissolves in the blood, starting a reaction between two proteins, leading blood clots to form to help stop bleeding. The approval means surgeons now have an extra option to help control bleeding during surgery when needed.

The spray-drying process used to manufacture Raplixa produces dried powders that can be combined into a single vial, eliminating the need to combine the fibrinogen and thrombin before use and allowing the product to be stored at room temperature. Commercial supplies of Raplixa are now being manufactured by Nova Laboratories.

Case study 2 – Aseptic spray drying in human plasma manufacture

Entegrion is a US-based life-sciences company that develops and delivers products that address unmet needs in military healthcare. It has developed a proprietary dehydrated, pathogen-inactivated human plasma called Resusix that is based on aseptic spray drying technology. Entegrion has partnered with Nova to manufacture the product. The Resusix programme is funded by the US Office of Naval Research (ONR) and is currently at Phase I clinical trial stage.

The current practice for treatment of patients with severe haemorrhage is to supplement coagulation factors and volume replacement using frozen plasma. One of the major drawbacks of using frozen plasma is the time it takes for preparation. In comparison, dehydrated spray-dried plasma can be rehydrated, and ready to use within minutes. The longer shelf stability enabled by aseptic spray drying manufacturers breaks the cold chain restrictions and makes this an attractive alternative for field and emergency use.

The manufacture of Resusix clearly illustrates some of the advantages of aseptic spray drying. Blood plasma is a complex mixture of proteins such as albumin, globulins, fibrinogen, clotting factors and hormones. It has been demonstrated that the biological activities of all these components are minimally altered by the spray drying process.

Bone cement filling under isolator conditions

Bone cement filling under isolator conditions

Resusix consists of pure plasma, without the need to use any stabilisation excipients – a further benefit of the gentle nature of spray drying. Since the aseptic spray drying process is a continuous process, this technology allows Entegrion to meet its high commercial expectations, which may not have been possible with alternative drying methods.

As the product is administered directly into the bloodstream, it must be of injectable-grade quality. By using aseptic spray drying, Nova can manufacture and securely package the product under truly aseptic conditions – removing the need for a final sterilisation step and thereby reducing time and cost.