Pharmaceutical production processes and quality-assurance laboratories commonly use high-purity nitrogen for various purposes, such as gas chromatography, sample drying, and protecting compounds from the deleterious effects of oxygen or water vapor. Many facilities buy compressed gas tanks or evaporate liquid nitrogen to supply these processes with dry, high-purity nitrogen. An in-house nitrogen generator, however, provides several significant benefits.

An in-house generator typically is designed to remove particulate matter, compressor oil, water vapor, and oxygen from laboratory air to provide highly pure nitrogen. The system employs a coalescing filter to remove trace liquids and particulate matter. A pressure-swing adsorption system that contains a pressurized-carbon molecular sieve adsorbs nitrogen, but not other gases. Users deliver the nitrogen to the production or quality-control system by removing the pressure on the molecular sieves. 

Generating nitrogen in house can help increase safety in a facility. An in-house generator is designed to supply the gas at the pressure and flow rate required for the desired operation, and employees can adjust these parameters at any time by turning a knob. In contrast, a compressed-gas tank contains the gas at a high pressure. If the valve on such a tank is compromised, the gas could displace the air in the facility, thus potentially asphyxiating the employees working there. A compressed-air tank also must be replaced from time to time, and if a technician loses control of the tank while it is being moved, a serious accident could occur. Finally, employees that use liquid nitrogen to generate nitrogen gas run the risk of getting frostbite.

In-house nitrogen generation also is convenient for many facilities. Once an in-house generator has been installed, it can provide the desired gas for 24 h per day and for seven days per week without additional effort. In contrast, compressed-gas tanks and liquid-nitrogen containers require the operator to ensure that an adequate supply of the gas is available for the task at hand. Sometimes operators must change the supply at an inconvenient time. For example, compressed-gas tanks typically are stored in external facilities, and it may be inconvenient to replace them, especially in inclement weather.

Facilities also may be able to decrease their costs by using in-house nitrogen generators. These units extract the desired nitrogen from the air and, once they have been installed, do not entail any costs beyond electricity and annual maintenance. Many users report that these units pay for themselves in a year or less, and that operating costs can be reduced by 50% or more. If a site uses compressed-gas tanks to supply the nitrogen, it must consider the cost of each tank as well as other costs, including those of demurrage, the time required to install the tanks periodically, the paperwork to order tanks, and inventory control. 

In addition, in-house generators can help decrease a facility’s energy requirements. An in-house generator operates on a normal 15 A circuit and consumes a small amount of power (e.g., a few hundred watts). In contrast, compressed-gas tanks and liquid-nitrogen tanks require a significant amount of energy, including the energy needed to pressurize, compress, and transport the gas to the point of use. An in-house nitrogen generator also can provide greenhouse-gas benefits because it does not need to be compressed and transported to the point of use. 

Benjamin Chal, a process-development engineer at MedImmune, a manufacturer of vaccines and monoclonal antibodies, is a typical user of an in-house nitrogen generator. Chal has used various Parker Balston nitrogen-generation systems to provide the necessary gas for several years. Recently, he installed a Parker Balston DB-20 system to provide a flow rate of approximately 300 L/min of nitrogen to convert liquid formulations into dry powders (i.e., through lyophilization and spray drying) for long-term storage stability.

The DB-20 nitrogen-generation system produces a flow of nitrogen as great as 173 standard ft

/h at 99.99 % purity. The unit can achieve higher flow rates for nitrogen gas of lower purity (e.g., a flow rate of 2250 standard ft

/h can be obtained if 95% nitrogen is acceptable). The system operates at pressures as high as 80 psig. The resulting nitrogen has a dew point as low as –40 °F and includes no particles larger than 0.01 µm. An optional oxygen monitor with alarm relay outputs can be supplied to alert the user to open a backup supply or otherwise protect the sample. “The nitrogen-generator systems are very reliable; once the generator is installed, a continuous nitrogen supply of consistent purity is available within minutes from startup, and all service and maintenance can be performed on an annual basis,” reported Chal.

Compared with tanks, in-house nitrogen generators provide several significant benefits to a facility, such as increasing the safety of handling the gas. The units produce nitrogen at the precise flow rate and pressure required. In contrast, when high-pressure tanks are employed, various safety issues must be considered. In addition, an in-house generator provides significant cost savings and has a lower environmental footprint than tanks do.

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Articles

In the Mixer

Many facilities buy compressed gas tanks or evaporate liquid nitrogen to supply processes with dry, high-purity nitrogen. An in-house nitrogen generator, however, provides several significant benefits.

In-House Nitrogen Generation Can Enhance Safety and Decrease Costs

Growing interest in continuous drug manufacturing has brought greater attention to in-line blending, a process that the petroleum and fine-chemicals industries have used for decades. In-line blending entails feeding ingredients continuously into a mixer that generates a homogenous blend without interruption. The blender is meant to run for extended periods, but it typically contains only a small amount of material at a time. Like other continuous processes, in-line blending promises to yield products of consistent quality, increase efficiency, and reduce the manufacturer’s costs.

The pharmaceutical industry has used in-line blending to add powders to liquid formulations for five to 10 years, says Matt Chapas, manager of manufacturing science and technology at Ben Venue Laboratories. But the process also can blend liquids together quickly and easily, and it could potentially be used to manufacture a global vaccine continuously. In addition, companies are showing increased interest in using in-line blending to mix free-flowing powders continuously, although not many drugmakers have used the process for this application.

One advantage of in-line blending is that it relies on simple equipment and does not require tanks or agitators. Static mixers (tubular devices with no moving parts) contain mixing elements that promote radial dispersion as materials flow around them. Manufacturers can set up an in-line blending operation by installing static mixers in a pipeline. Valves, flow meters, positive-displacement pumps, and metering pumps are all necessary to control the flow of material accurately. In many cases, a drugmaker can use its existing equipment for the process, says Art Etchells, an independent consultant and DuPont fellow 

Some manufacturers have realized that in-line blending can greatly increase the wetting of powders and enable enhanced and consistent solubilization. When operators manually introduce powders that are difficult to dissolve into liquid formulations, the powders sometimes pool on the surface. “In-line blending could potentially resolve these issues without extending mixing times or requiring the addition of nonaqueous solvents,” says Chapas.

The process also can help provide the containment needed to work with cytotoxic drugs. In-line blending limits potential exposure to the active in a powder state to the material-loading step. Ben Venue worked with a leading supplier to design disposable isolators that operators use when loading the in-line blending hopper, thus reducing the potential for operator exposure to highly potent actives. 

Perhaps the biggest advantage of in-line blending is that it lets operators control the rate of ingredient addition consistently, thus allowing great control of the blending process. The approach “could result in more consistent and reproducible blending processes, as well as an optimized process from an efficiency standpoint,” says Chapas.

Although in-line blending is best suited to continuous operations that produce large volumes of drug, companies could use the technique for batch processes, too. For example, operators may want to add a hydrophobic powder such as magnesium stearate to a suspension as it is being milled. Dumping the powder into the liquid usually produces an undesirable mixture of powder, air, and liquid. “The way to break those bubbles containing powder is to apply shear,” says Fernando J. Muzzio, member of 

’s editorial advisory board and director of the National Science Foundation’s Engineering Research Center on Structured Organic Particulate Systems at Rutgers University. “One way to do it effectively is to use an in-line mixer that provides that shear to induct the powder gradually, force wetting, and displace the air. That is an application done in batch. We have built tanks like that for pharmaceutical companies to help them solve those kinds of problems,” says Muzzio.

Several companies also have decided that it makes sense to mix continuously when the mixture will be roller compacted, even in a batch system. If operators have to lubricate product after it comes out of the roller compactor and before it reaches the tablet press, “it’s natural then to say, ‘All right, we can use an in-line mixer, we can add the magnesium stearate, and we can go straight into the tablet press and save a lot of headaches,’” says Muzzio.

In-line blending can accommodate process analytical technology to help deepen understanding and enhance control of manufacturing operations. The method can thus please regulators and drugmakers alike. Considering in-line blending’s other advantages and its applicability to continuous and batch processes, increased attention to the technique could well widen its popularity within the pharmaceutical industry.

Production Lines

Growing interest in continuous drug manufacturing has brought greater attention to in-line blending, a process that the petroleum and fine-chemicals industries have used for decades.

The Rise of In-Line Blending

Q: We are making an emulsion using a high-shear in-line mixer. First we prepare the aqueous phase, which includes an emulsifying agent and the active ingredient. Then we add the discontinuous phase, which comprises organic solvents and a monomer, to the vessel, and the in-line mixer is used in a recirculation line to form the emulsion. It’s a 60-gal batch, and it’s taking nearly an hour to get the results we’re looking for. We have tried changing the in-line mixer’s workheads to a two-stage configuration, but it doesn’t affect the mixing time. Where are we going wrong?

A: If you’re adding the discontinuous phase to the aqueous phase in the vessel, the chances are that your in-tank agitation is the problem. The agitator blades are probably positioned near the base of the vessel, which is running fairly slow to avoid aeration because oxidation can damage the active ingredient. But as you add the discontinuous phase and the liquid level rises in the vessel, the agitator won’t be capable of premixing the two phases. Instead, the in-line mixer is drawing the aqueous phase from the bottom of the vessel and recirculating it back into the top, while the solvents remain on the surface. Switching to a two-stage in-line mixer will increase shear, but not solve the problem, as you experienced. The ideal way to prepare an emulsion of this sort is to add the discontinuous phase to the recirculation loop through a manifold just before the in-line mixer, so that both phases are mixed on contact in the mixer’s high-shear zone. However, if you have to add the two phases to each other in the vessel, make sure the in-tank agitator is premixing them properly. Speeding it up as the liquid level rises to maintain the required in-tank movement should allow it to form a rough premix. The in-line mixer will then be able to subject this premix to intense shear and reduce the droplet size to form a finely dispersed, stable emulsion more quickly. 

—Peter Matthews, technical manager of Silverson Machines

If you have a problem with your equipment or process, an industry expert may have the solution. Please send your question to 

 and we may be able to provide an answer in a future issue. All questions will remain anonymous.

Troubleshooting

We are making an emulsion using a high-shear in-line mixer. It?s a 60-gal batch, and it?s taking nearly an hour to get the results we?re looking for. We have tried changing the in-line mixer?s workheads to a two-stage configuration, but it doesn?t affect the mixing time. Where are we going wrong?

An Exhausting Emulsion

Emerson Process Management
 Filling transmitter increases accuracy


 Emerson Process Management’s Micro Motion filling-mass transmitter uses Multivariable Digital technology and a Coriolis sensor to perform high-speed, accurate filling. The device can accommodate fills that last less than 1 s and challenging fluids, such as those with entrained air, suspended solids, or high viscosity. The unit’s integrated valve control is designed to reduce external processing and increase accuracy. The transmitter is suitable for various linear and rotary filling machines in the life-sciences industry.

The Filling Mass Transmitter delivers mass, density, and temperature process data, thus supporting continuous monitoring of product quality with a real-time view of fluid characteristics. The unit’s digital communications capability enables real-time quality control and on-the-spot changes to fill targets or recipes.

In addition, the transmitter’s automatic overshoot compensation adjusts valves in response to changes in process conditions (e.g., delivery pressure and fluid characteristics). This feature enhances the unit’s accuracy and reliability and reduces setup and maintenance requirements.

Spirax Sarco
 Sanitary valve prevents cross contamination


Spirax Sarco’s CVS10 sanitary check valve is designed to open when media exerts pressure on it. The valve has an internal spring-cracking pressure of 0.507 psi, and when media stops flowing, the spring’s force closes the valve before reverse flow and cross contamination can occur. The valve helps protect equipment from pressure surges associated with hydraulic forces, such as waterhammer. In addition, the device has a high flow coefficient and causes minimal pressure loss.

The CVS10 valve is available with a metal seat for clean- and pure-steam or condensate applications. A soft-seat version also is available for high-purity water and liquid applications, such as water-for-injection systems. All wetted materials throughout the valve are fully traceable.

In addition, clients can choose from various surface finishes, including a finish as low as 15 microinch Ra electropolished. Low surface finishes help to maintain sterility in the system by reducing the risk of microbial growth in crevices on the valve’s surface.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the February 2011 edition from Emerson Process Management and Spirax Sarco.

Equipment and Processing Report-03-16-2011

In-House Nitrogen Generation Can Enhance Safety and Decrease Costs

The Rise of In-Line Blending

An Exhausting Emulsion

March 2011 Editor's Picks: Products from Emerson Process Management and Spirax Sarco