Fluid control for demanding pharmaceutical applications

Nov. 2, 2022
Modern pharmaceutical processes benefit from fluid control devices that easily control a diverse range of flow rates, have high precision and respond in milliseconds to manage pulsating environments.

With the development of mRNA vaccines and other drug products related to COVID-19, the pharmaceutical industry has experienced dramatic advances in recent years. As researchers and engineers continue to explore ideas, they sometimes encounter fluid control challenges that cannot be met with traditional instruments and systems. 

Several types of valves are available to address the pressure or flow control needs of a given pharmaceutical application. Popular choices include control valves or spring-operated stem valves, which control fluid through area restriction on a stem using force balancing. Diaphragm valves have been used in similar ways, as well as for on/off applications. 

Despite a variety of options, it can be difficult to find suitable fluid control for modern sanitary applications that have increasing performance needs as drug products become more complex to manufacture. Modern pharmaceutical processes benefit from fluid control devices that easily control a diverse range of flow rates, have high precision and respond in milliseconds to manage pulsating environments. Furthermore, Pharma 4.0, the initiative of the International Society for Pharmaceutical Engineering (ISPE), encourages the automation of devices to gather more insight about process data and gain more control over versatile systems that can produce a variety of drug products. 

An innovative approach

For these complex fluid control challenges that are prevalent throughout the pharmaceutical industry, a dome-loaded multi-orifice valve or regulator set through 1:1 pneumatics is often capable of performing reliably despite multiple difficult conditions. 

The unique design of this device results in an exceptionally wide flow rate range that can offer solutions for even the most extreme fluid and pressure control scenarios. A frictionless and supple diaphragm avoids hysteresis, allowing for superior precision and virtually instantaneous reaction. The instantaneous reaction time coupled with the pneumatic pilot further allows for pressure pulsation dampening, which is prevalent in many sanitary pump technologies. Moreover, these devices are easily automated using an electronic pressure controller to set the dome pressure, which integrates well with the Pharma 4.0 push in the industry.

How a dome-loaded multi-orifice valve works 

Diaphragms have been used in valves and regulators to sense pressure and actuate valve movement for many years. Traditionally, these valves use the diaphragm to seal against a weir, often for on/off service. Diaphragm valves are popular in the pharmaceutical industry because they offer an unobstructed path for smooth flow and cleanability and are an easy item to replace for preventative maintenance.

A dome-loaded multi-orifice valve is a newer type of diaphragm valve in which a thin membrane covers a field of parallel orifices. Inside the valve, the diaphragm is positioned between the main body and the reference cap. The main body contains orifices that are covered and sealed by the diaphragm when they are not engaged.

As the name implies, the valve is dome-loaded. It is controlled with pneumatic pilot operation at a 1:1 ratio, which means that gas or air is fed into the top (dome) area of the valve to provide the pressure setpoint for the process. This is similar to the way a spring-operated valve uses the spring compression to generate the setpoint. The pressure of the gas in the dome is set by a secondary standard regulator called a pilot regulator. The pilot regulator can be manual or electronic, depending on the application’s requirements.

As fluids flow through the unit, the thin and supple diaphragm lifts off the orifices to release pressure once the setpoint is reached. When flow is minimal, only a portion of one orifice will open to release the pressure. When flow is high, the diaphragm is pushed up to engage more orifices. The responsiveness and flexibility of the diaphragm engaging with the multiple orifices result in an extremely versatile flow rate range. 

Every part of these dome-loaded multi-orifice devices can be made from selected materials to meet chemical, temperature and pharmaceutical industry standards. The large turndown works well for back pressure, flow control and vacuum applications.

Sanitary considerations

For sanitary applications, dome-loaded multi-orifice valves and regulators are configured to meet drainability, cleanability, surface roughness and other requirements specified by the American Society of Mechanical Engineers: Bioprocessing Equipment (ASME BPE) standards. Wetted materials meet United States Pharmacopeia (USP) standards. Pulsation dampening is an inherent feature of the design, which is of benefit when considering the wide use of positive displacement pumps, which are naturally pulsating. For more extreme downstream pulsation dampening needs, optional enhancements may be selected.

In addition, single-use multi-orifice dome-loaded valves that can be gamma irradiated are available for the growing single use segment of the biopharmaceutical manufacturing market. 

Application example #1: Pressure control for Active Pharmaceutical Ingredient reactors

Since pressure control often plays an important role in optimizing chemical and physical reactions, it is not surprising that it can be particularly useful for Active Pharmaceutical Ingredient (API) manufacturing, which relies on carefully controlled chemical reactions to ensure the purity of crucial drug ingredients.

API manufacturing sometimes uses flow chemistry to run a continuous process through a reactor. In this scenario, accurate and reliable pressure control is beneficial for phase control, residence time, reaction speed and equilibrium management. As the reaction evolves, changing thermodynamic factors can fluctuate, requiring stable control regardless of short- and long-term needs. 

A dome-loaded multi-orifice back pressure regulator (BPR) has several advantages over traditional BPRs for flow chemistry applications because it controls over a wide flow range, offers improved precision, provides instantaneous control and can handle extreme temperatures and corrosive chemistries as well as the multi-phase flow found in some API manufacturing. For API products that are crystalline in structure, such as lithium salts that have a tendency to clog, the multiple orifices can extend the operating time by allowing more flow paths. If one orifice begins to restrict, the remaining orifices compensate for the change in flow to allow for continuously smooth and accurate pressure control. 

Application example #2: Pressure control for chromatography columns

Pressure control plays a similar role in the chromatography step of biopharmaceutical processing.

Pharmaceutical chromatography columns are typically packed with delicate resin beads to retain desired components (such as antibodies in affinity chromatography) or filter out undesired compounds (such as protein A in ion exchange chromatography). 

Some common challenges for chromatography skids include: 

  • Precisely controlling flow rates across a wide range. Gradient buffer additions, for example, have 100:1 turndown requirements.  
  • Providing consistent back pressure to prevent bubble formation, which could prevent resin contact, reducing effectiveness of the tightly controlled packing of the column. 
  • Managing pulsations from a positive displacement pump, which can disrupt resin packing and create uneven flow channeling that results in inefficient processing.

A dome-loaded multi-orifice BPR can improve the chromatography process by reducing pulsations in the feed. The supple diaphragm naturally responds to slugs of fluid moving through the valve, and the ultra-wide flow coefficient (Cv) range allows it to keep up with positive displacement and diaphragm pumps, in addition to handling viscosity or varying flow rates during the phases of chromatography. Passive dampening inserts in the BPR minimize pressure pulsations downstream of the regulator. The result is fewer pressure spikes, significantly reducing damage to sensitive cells or costly coated resins, and maintaining even packing density. In contrast, many traditional spring-loaded designs are slower to react when conditions change due to flow and viscosity fluctuations.

Application example #3: Vacuum drying for API manufacturing

For powder or crystalline APIs, drying is often one of the final manufacturing steps.

Vacuum ovens are frequently used to dry pharmaceutical ingredients. Benefits to using vacuum conditions include: 

  • Lower pressure allows efficient drying at lower temperatures, which benefits products that cannot withstand high temperatures.
  • Stable vacuum can help remove entrapped liquid and obtain low final moisture content.
  • Vacuum serves to remove targeted solvents from the system by precise vapor pressure control. 

Process automation, precision vacuum control and the ability to handle harsh chemicals are important design factors in API vacuum drying. 

Spray drying is one of the steps that can be used in the overall drying process. In this situation, the API is combined with a volatile solvent to assist drying. To remove the solvent and complete the drying process, the API is sent to a vacuum drying vessel, often under a nitrogen blanket, with an agitator and heating system. Consistent vacuum must be maintained for efficient drying and removal of volatile solvent gasses for recovery. 

 A dome-loaded multi-orifice vacuum regulator combined with an electronic pilot setpoint controller maintains precise and consistent vacuum control despite changes in flow or moisture conditions during drying. As solvent is boiled off due to the vacuum pressure, flow rate will decay, requiring the control valve to have high turndown to compensate for the near-zero flow rates as the remaining solvent is boiled from the system. Additional advantages of the device are that it can be manufactured with chemical-resistant materials to accommodate solvents and it is easily automated.

Other pharmaceutical uses of dome-loaded multi-orifice technology

The synergistic design elements of dome-loaded multi-orifice valves and regulators enable them to elegantly meet the complex process requirements of a wide range of pharmaceutical applications in addition to the examples above. For buffer dilution, immediate precision flow control over complete gradient range increases the rangeability of buffers produced for a given footprint. In filling applications, fast and precise pressure control in recirculation leads to more precise filling by avoiding over/under filling cases and can measurably impact total product yield. For millibar pressures in tank blanketing and bioreactor headspace control, the instantaneous response maintains pressure to preserve a healthy environment for sensitive cell cultures in the bioreactor, which undergoes varying sparging conditions throughout the process.


For many pharmaceutical processes, traditional valves and regulators continue to offer robust fluid control for a variety of applications. As processes evolve to meet the needs of manufacturing new life-saving products, however, dome-loaded multi-orifice technology can often provide solutions that were previously not possible. Specific advantages include:

  • Millisecond native response to quickly varying conditions.
  • Exceptionally wide Cv range.  
  • 1:1 pneumatic operation, allowing for easy automation.
  • Extremely low flow rates (controls Cv down to 1E-9).
  • Design flexibility allowing for material selection compatible for virtually any fluid.

Because they are able to control back pressure, vacuum and flow, these unique devices are worth considering for a variety of complex pharmaceutical applications.  

Ryan Heffner, PE, is single use technology manager for Equilibar, a specialty fluid control technology company based in North Carolina. He has expertise in designing valves and back pressure regulators for the pharmaceutical industry, particularly for the rapidly growing sanitary single use market.  He may be reached at [email protected] 

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