With more of our new drugs and pharmaceutical products now being produced and developed in bioreactors and incubators, there is increasing need for gas delivery systems and pressure regulators that not only perform the function required but that also comply with materials of construction, traceability, and supplying high-purity uninterrupted supply of critical gases to these processes. To that end, the FDA’s promotion of Quality by Design (QbD) as an integral part of drug manufacturing bears careful consideration when selecting and looking at options for gas control systems and pressure regulators.   

This article will focus on key factors impacting the choices in regulators and controls for oxygen:

• Materials construction compatibility.

• Materials conformance and traceability.

• System automation options with gas control.

• QbD and gas controls.   

Materials of Construction Compatibility

Decisions regarding selecting appropriate regulators and gas control systems should start with making sure that the materials of construction of the devices are compatible with the gas, flow, and pressure required. It is not a “one type or material fits all” evaluation, and a line must be drawn between what is desired and what works. When dealing with delivering Oxygen to a bioreactor or oxygenating process, the flows required are typically rather large, 2,000 cubic feet per hour, compared to the 1 liter per minute required for running a Total Organic Carbon analyzer (TOC). Both require that the regulator materials of construction and their cleanliness be compatible with oxygen.

Accordingly, what is referred to as “soft goods” seats or seals should be Oxygen-safe, PTFE (Teflon®), or perhaps PCTFE (Kel-F). The regulator body for the bioreactor would preferably be 316L stainless steel, as it will need to be in the process areas. Design should adequately allow for the kind of flow required.  Selecting a regulator with a Cv (flow coefficient) of 1.0 and certified cleaned for Oxygen service to a recognized standard, such as CGA G-4.1, appropriate seat materials, 316L stainless steel body, diaphragm, and wetted materials, with a balanced valve design allow for high flow at varying inlet pressures.


Figure 1: With PCTFE seat materials, PTFE diaphragm seals, 316L stainless steel body, diaphragm and wetted internals, and Isoflow™ balanced valve design, CONCOA’s Series 484 regulators deliver high-purity gases at high flows in pharmaceutical applications

These materials of construction would also be compatible with corrosive gases such as gaseous Hydrogen Chloride as well as inert high-purity gases like Nitrogen or Helium. Using a unit with oversized seat design, however, that allows for high flow at varying inlet pressures on the minimal flow of Oxygen required for the TOC analyzer is unnecessary because the design would result in too great a variation in delivered pressure.  Typically the gas would be delivered in high-pressure cylinders with brass cylinder valves as apposed to cryogenic form in large bulk tanks that feed the facility.

Moreover, since the instrument would be located outside of the process area, the need for it to be 316L stainless steel body design may be an expense that would be halved by using a high-purity bar stock brass design with the same minimum diaphragm and soft goods requirements that meet Oxygen’s compatibility and cleanliness standards. 

Materials Conformance and Traceability

Whenever a regulator or system is destined for or may be used in Oxygen service, the device should be supplied from the manufacturer with a Cleaned for Oxygen Service certificate stating the standard and the maximum operating pressure of Oxygen to which the unit conforms.  The 484 Series shown in Figure 1, for example, though typically used for pipeline point of use pressure control, is designed to withstand a maximum inlet pressure of up to 3000 psig of Oxygen and is cleaned to a standard for that. Additionally, the design is tested to EN ISO 2503, the Adiabatic Oxygen Ignition Test certifying the design withstands ignition at 1.5 times the stated operating pressure. This is a critical conformance that the design is safe for use with Oxygen at that pressure.   Regulators used in the process stream as in the case above should also be available with a certificate of what the wetted parts are and, if required, a traceability certificate of Materials of Construction.

All stainless steel today, thanks to globalization, may not be created the same. In examining the traceability documents of such materials, the original mill source should be part of the evaluation process. That the source is credible and well established should be a key consideration. Soft goods should be in conformance to USP Class VI materials and Generally Recognized as Safe by the FDA, referred to as “GRAS.”  When it comes to requiring this of a regulator for Instrumentation gases, however, a word of caution:  Such a prerequisite would incur costs that may yield nothing in return.

System Automation with Gas Control     

When it comes to gas pressure control in most pharmaceutical processes, critical factors are continuous supply and steady, precise pressure control. If the correct regulator at the point of use is chosen, this should be as simple as setting the pressure desired and just monitoring the regulator’s performance with pressure transducers.

Wired or wireless communication now offers many monitoring options.   Take, for instance, the levels in your bulk supply side.  Most levels depend on the type of system the gas supplier installs.  The supplier has additional information on the system and controls the information dispensed. 

Wireless telemetry monitoring presents problems of communicating over distances and reliability, as well as significant cost per unit and per month in fees. For critical gas supply, there should be a reliable backup particularly if it is supplying Carbon Dioxide gas to incubators or Oxygen to those bioreactors. For such critical backup, real-time monitoring and control are needed.  With most systems moving toward computerization and instant access via networks and remote, real-time information, the logical progression is to have these functions also networked with their own Web server.


Figure 2: An example of computerized gas control, Series 542 High-Flow Backup Systems come standard with an onboard Web server and software for monitoring and programming.

Exemplifying computerized gas control is the high-flow backup system shown in Figure 2 that comes standard with an onboard Web server and monitoring software. Status of what the primary pipeline pressure and reserve status is available 24/7 real-time with data logging of events and password control the functions of the system that can be configured remotely. The device emails both alarm status and “events” as desired or programmed. Its failsafe design guarantees reliability of supply to process that can never be without gas supply. In a user friendly display format that is easy to format and reliable, it is the latest in the line of IntelliSwitch™ “smart” gas control systems. Monitoring and engaging a reserve supply before any variation in the supply to point-of-use applications are done with an onboard computer and Web server, which is not subject to monthly fees or access to someone else’s hosting. The user has control and access 24/7.

The logical next step would be to integrate other pressure control devices with similar capabilities so that desired parameters can be programmed, monitored, and controls initiated.  Perhaps this next step is a smart regulator that by itself is programmable to vary or maintain set parameters driven by the process activity and selectable programming.


Quality by Design and Gas Control

The FDA’s promotion of QbD in drug manufacturing, simply put, is:


• Get it right first.

• Design to achieve the end product performance and yield.

• Continually monitor and update the process.

This contrasts with what has been the standard of a fixed process that relies on batch analysis or end-product testing that often leads to high waste and the inability to understand what went wrong in a given process.

The QbD environment begs a key question:  Should not the devices that control critical functions, such as pressure regulators, also be produced under a similar quality control system in which their design enables them to be continually monitored and to react to the desired end result of delivering their critical ingredient into the process?

To a great extent the first part of QbD has long been the basis of pressure regulator design and conformance, as most designs prior to release must pass testing for compatibility, endurance or cycle life, and resist failure under extreme pressure as with those destined for Oxygen service. There are international standards for regulator design and performance testing.  The Compressed Gas Association (CGA) E-4 standard covers this, and most manufacturers do specific product performance testing as part of assembly and quality control of production. Challenging resistance to failures as with testing to EN ISO 2503, Adiabatic Oxygen Ignition, essentially proofs a design prior to use in hazardous conditions.  Recently the FDA put forth a guidance covering Oxygen regulators for patient use that will be moving that end of the regulator industry toward QbD and risk assessment, the first change in many decades for these devices.  Testing of these devices must include testing with gas at the expected or stated pressures, as well as performance of delivered pressure against the design standard, with the end result continually improving against that standard.

Such guidance then begs another question:  Should not that apply to the standards for regulators that control drug yields and quality? It is not an option to have defective devices or less than acceptable devices released for use. But to monitor post-production performance and adjust that performance in use becomes the challenge that faces today’s manufacturers of regulators and gas control systems. Perhaps the start can be seen in the use of computerized “smart” systems.

The ability to monitor, change programmed functions, and log events as an independent, networked device should be the start of moving gas pressure control toward such devices being integral to drug manufacturing’s QbD, via integration and information accessible in real time and acted on using programmable functions.

About the author:

Larry Gallagher is Specialty Gas Products Manager for CONCOA, Virginia Beach, Virginia, manufacturers of gas pressure and flow control equipment for industrial, medical, and specialty gas applications, as well as distribution systems for laser materials processing, (800) 225-0473,,