Henrik Schwartzbach is a Senior Process Technologist at GEA Niro.

Henrik Schwartzbach

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: 					

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

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 H

, which is approved by both the FDA and the EMA. For spray dryers, H

 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. H

 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. 

Senior Process Technologist at GEA Niro 			

Articles

Henrik Schwartzbach, senior process technologist at GEA Niro, explins why spray drying is seeing increased uptake in the pharma industry.

Achieving Aseptic Drying With Spray Drying Technologies

Taking a risk-based approach to product quality is an excellent way to uncover potential weaknesses in process designs or control strategies. A risk assessment is different from an impact assessment because the former considers the severity and the likelihood of the impact. A properly performed risk assessment is a valuable tool in designing experiments, defining design space, and planning design-of-control strategy. The ultimate goal of risk assessment is not only to achieve the desired quality, but also to produce predictable and consistent quality. 

Target product quality and product-quality consistency

The target product quality in this instance may be the desired product quality for full-scale production or a quality that is sufficient for the current scale and stage of development. Product-quality variability is a common problem that can be difficult to solve. Product-quality risk assessment is an effective tool to reduce product-quality variability.

The first stage of performing a risk assessment is identifying potential hazards. A hazard is something that influences the process directly or indirectly (e.g., materials of construction or instrumentation). A typical impact assessment will identify hazards, the type of hazards, and the documentation required such as material or calibration certificates.

Impact assessments are typically designed to identify potential hazards, but not the severity or frequency of exposure to the identified hazards. Since neither the severity nor the frequency of the hazards is identified, an impact assessment is inadequate for designing future experiments or control strategies.

Risk is a combination of the severity of exposure to a hazard and the frequency of being exposed. Being struck by lighting is a good example of a low-risk hazard. Despite the severity of the hazard, the likelihood of it happening is small. 

A product-quality risk assessment requires both product and process understanding to be performed effectively. Consequently, it is best performed after process development has been completed. Ideally, the target product quality is known at that point, including the extent to which the different product-quality attributes can vary without unacceptable quality loss. The limits of acceptable variability are rarely known for all product attributes, however. A quality risk assessment can often identify the aspects of the process that require further investigation. Quality risk assessment must be included in the experimental design or receive special attention in the control strategy. 

It is important that personnel have adequate general understanding of the process type (in this case, spray drying), especially if the process will be scaled up at a later stage. 

An ideal control strategy would allow large input variation but maintain low output variability. Unfortunately, these criteria are rarely met in the real world. A good control strategy would allow some input variation, maintain low output variability, and provide early warning of deviations. The success of such a control strategy is ultimately limited to known input variation. Process analytical technology (PAT) is a valuable tool in identifying input variation that previously was overlooked or deemed insignificant (because of multivariate effects, for example). 

The control strategy can be simplified if the product-feed variations are small, as they frequently are. In this case, a good control strategy is to fix the process parameters that have the greatest product-quality impact by controlled variations in the process parameters with the least product-quality impact.

In a spray dryer, a liquid feed (e.g., solution, suspension, or emulsion) is atomized into a spray of fine droplets and suspended in gas while drying. Spray drying is a fast method of drying because of the product's large surface area and high heat-transfer coefficients. The product's large surface area also enables drying at low to moderate temperatures. The rapid drying and consequent fast stabilization at moderate temperatures make spray drying feasible for heat-sensitive materials.

Spray dryers must always be cleaned and sometimes sterilized. These and other subprocesses are often as critical as the main drying process, but are not part of the assessment as described below.

Identifying the important process parameters

In a spray dryer, droplets or particles are dried while they are suspended in the drying gas. During the drying process, heat is transferred from the drying gas surrounding the droplets or particles, and solvent evaporates from the droplet or particle surface into the surrounding drying gas (see Figure 1). The process also involves various complex diffusion processes, most of which are specific to the product–solvent combination used. This complexity makes liquid-feed composition an important part of early process development. Because the liquid-feed composition rarely can be used for process-control purposes, however, the parameters available for process control are drying temperature, drying-gas humidity, and droplet size.

The conditions under which the droplets are transformed into particles influence the final solvent content and the particle morphology.

In a spray dryer, it is important to distinguish between dryer-inlet temperature, product temperature, drying temperature, and dryer-outlet temperature. In a well-designed cocurrent spray dryer, the intense mixing of spray and drying gas results in fast cooling of the drying gas by the evaporation of solvent. The end result is that the temperature in the drying chamber is practically equal to the spray-dryer outlet temperature. This parity can be measured and calculated with computational fluid-dynamic models (see Figure 2). 

Because of the evaporation of solvent from the product, the droplet or product temperature remains lower than the spray-dryer outlet temperature during the entire drying process. The droplet or product temperature also remains lower than the spray-dryer outlet temperature in the high-temperature region at the drying-gas inlet, where the rate of evaporation is at its highest and the droplet temperature is at its lowest (i.e., approaching the wet-bulb temperature). The product temperature at the discharge is typically between 5 and 20 °C colder than the drying-gas temperature at the outlet.

The importance of the drying-gas temperature at the spray-dryer outlet is clearly seen in experiments where the correlation between product characteristics and outlet temperature is stronger than most other process variables. The outlet's drying-gas temperature is usually fixed at a product-specific set point by a feedback control loop. The feedback loop normally adjusts the inlet's drying-gas temperature or the liquid-feed rate to maintain the outlet's drying-gas temperature at the set point (see Figure 3).

The solvent-vapor content in the drying gas is the sum of the solvent-vapor content in the inlet drying gas and the evaporated solvent. In most applications, the evaporated solvent is the major contributor. Because the evaporation rate is proportional to the difference between the inlet and outlet drying-gas temperature, an increase in the inlet drying-gas temperature (at constant outlet drying-gas temperature) results in an increase in drying-gas solvent-vapor content.

The control of the inlet's drying-gas temperature depends on the control strategy applied for the outlet's drying-gas temperature. When the outlet drying-gas feedback loop adjusts the inlet's drying-gas temperature, the fixed set point for the liquid-feed rate indirectly sets the inlet's drying-gas temperature level (see figure 3). Alternatively, a feedback loop maintains the inlet's drying-gas temperature at the set point by adjusting the main process gas heater. 

The solvent-vapor content in the inlet drying gas is controlled effectively and accurately by adjusting the condenser's outlet gas temperature (i.e., the dew point of the gas). In applications that use ambient air as the drying gas, the condenser is replaced by a dehumidifier or sometimes completely omitted. 

Droplet size is controlled through the atomization process as long as suspended particles in the liquid feed are small compared with the droplets created. Atomization is a complex but reproducible process in which droplet size and droplet-size distribution depend mainly on the rheology of the liquid feed, the energy applied, and the liquid-feed rate. The atomization energy can be applied and controlled in various ways such as adjusting the speed of a spinning wheel in a rotary atomizer, the flow of a gas in a two-fluid nozzle, and the liquid-feed pressure in a pressure nozzle (see Figure 3). For a given pressure nozzle and liquid feed, the liquid-feed rate and the liquid-feed pressure are mutually dependent. Either of them can be used in a feedback loop to the feed pump to maintain constant atomization conditions and thereby constant droplet size and droplet-size distribution—as long as the liquid-feed rheology remains constant. 

Spray dryers are generally designed to work correctly within a limited range of drying-gas flow rates: typically ± 10–20%.  The process parameters that have been selected as critical above, however (i.e., inlet's drying-gas temperature, outlet's drying-gas temperature, and feed rate), are sufficient to calculate the heat and balance across the system. The drying-gas flow rate is thus a dependent process parameter, not a variable process parameter.

Though the drying-gas flow rate is a dependent process parameter, it is impractical to control it according to real-time mass-balance and heat calculations. A simple feedback loop between a gas-flow measurement and the main process gas fan works just as effectively. Gas-flow measurement in this case does not require an accurate absolute measurement: a reproducible relative measurement also suffices. 

Assessments of risk are relative. A risk's magnitude is gauged in comparison with other risks, and "high risk" is relative. 

 In most spray-drying applications, a strong, reproducible correlation exists between product quality attributes that are influenced by the process parameters and the basic process measurements (e.g., temperature, pressure, and flow). Basic process measurements are reliable. Regular calibration and preventive maintenance reduce the risk of deviations even further. The undetected failure of a process measurement or control loop is not likely. Because the process parameters must satisfy the heat and mass balance, an undetected error in one instrument would cause other process measurements to deviate from the normal values.

Process measurements and control loops are effective and reliable process controls and constitute a low risk. 

A few spray-drying applications do not exhibit an adequately reproducible correlation between the product-quality attributes that are influenced by process parameters and the basic process measurements. In those cases, the process measurements and control loops are not effective for controlling the process and constitute a high risk.

 Dried products' characteristics change with liquid-feed variations. The process impact of long-term variations in feed characteristics can be difficult to evaluate because the varations are complex and frequently multivariate. One problem is that a limited number of raw-material batches are used in product development, and some sources of variability are easily missed or deemed insignificant. 

The combination of control loops that rely on constant response to constant conditions and the difficulty in detecting and analyzing variations in the liquid feed make liquid-feed variations a moderate risk. 

In cases with simple liquid feeds (e.g., a solution of one simple chemical compound), the liquid-feed variations become a low risk. 

 Mechanical failures and assembly errors (e.g., missing or damaged gaskets) may cause contamination, deposits, or malfunctions that are not readily detectable. Operator training, standard operating procedures, and preventive maintenance reduce the risk of error, but a high risk of mechanical errors remains. 

 The process measurements and control loops are effective and reliable. A real-time heat and mass-balance calculation based on the process measurements is used to detect instruments that need calibration or certain liquid-feed abnormalities.

Spray-drying applications with an inadequate correlation between product-quality attributes and the basic process measurements require careful reevaluation of the process design space. The lack of correlation is frequently explained by the choice of a marginal or unsustainable operating point.

For example, an operation close to the limits for drying often results in particle agglomeration in the drying chamber and a high risk of deposits or irregular powder discharge (see Figure 4). Furthermore, single particles rarely have the same performance as agglomerates of the same size. The result is a poor correlation between atomization conditions and particle size because the drying conditions are marginalized typically by lowering the outlet drying-gas temperature. 

Process designs and control strategies can be improved by adopting a risk-based approach to product quality. The author describes how this approach can be applied to spray-drying operations.