Single-Use Standards Are Maturing, But The Process Remains King

A conversation with James Vogel, The BioProcess Institute

Navigating the "alphabet soup" of organizations setting standards for single-use systems — think ASME, USP, and ISO — is a never-ending game of whack-a-mole for bioprocess engineers.

While biopharma has borrowed heavily from the food and medical device sectors to establish foundations like universal connections and sterility assurance, true interchangeability remains a complex challenge, according to James Dean Vogel, founder of The BioProcess Institute.

Vogel argues that while the industry has hyper-focused on chemical concerns like extractables and leachables (E&L), it often overlooks critical physical risks, such as particulate generation in tubing and mechanical failures in pumps. As the cost of goods sold (COGS) becomes a higher priority in biopharma, the pressure to swap expensive equipment for interchangeable parts is mounting. However, engineers cannot simply rely on vendor certificates to ensure these parts work, Vogel says. They must validate that the equipment supports their process parameters.

Vogel agreed to sit down with us to preview these topics ahead of his upcoming presentation at Kivi Bio's interchangeability conference in Kenosha, Wisconsin, on January 21. He discusses the historical impact of the transition from ethylene oxide to irradiation, the industry's readiness for USP <665>, and why, regardless of the equipment used, "the process is king."

Could you start by explaining where things stand among various regulations and standards for single-use equipment interchangeability and testing?

Vogel: Standards are a constant evolution, and it's a chase as we try to align expectations and then come up with some structure that can generate standard practices. We call it the alphabet soup — all these acronym organizations that have been touching all sides of biopharma and bioprocessing.

Interchangeability evolved out of the food industry. Pharma doesn't really have as good a foundation as food. Food and beverage have had it from the beginning. We borrowed from them when we standardized on the tri-clamp to use as an example of a universal connection. It is by far not a perfect connection but was adopted as the best hygienic/cleanable connection at the time. Then single-use came. It began as a natural progression that entered the technical realm, adopting from medical devices. The big thing that really impacted this was moving away from ethylene oxide to irradiation —The residual chemical  (ethylene oxide) was no longer on the process/product contact surfaces

So, medical device made that change, and the costs of irradiation went down, and it allowed us to apply the same approach to bigger things. We can go from an IV bag with a 1/8-inch inner-diameter tube to, well, "Why not a 2,000 L bag and a 1-inch tube? Because now I can sterilize all that."

Regardless of whether single-use or multi-use, the key concern is regulation 21 CFR 211.65-Equipment Construction.

“Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.”

This includes all potential effects between the equipment and the process to make the drug. We have routinely focused on the process chemistry (pH, conductivity, chlorides, etc.), temperature (heat, frozen, etc.), pressure, mechanical stress (mixing, pumping, shear, etc.), and time of exposure.

How do we demonstrate that the equipment is not reactive, additive, or absorptive to alter the process?

Vogel: We also have to consider supporting processes, pretreatments, and their potential effects:

• Cleaning
• Sanitization
• Sterilization
  • Heat (autoclave and SIP)
  • Irradiation (gamma, X-ray…)
  • Chemical (ethylene oxide)

When the sterilization industry moved from ethylene oxide, that really opened the door for single-use. Over the last 15 years or so, we've been moving toward that.

But food and beverage have a distinct advantage over pharma. Their standard has been primarily 3A and a few others, like EHEDG for guidance. The Institute of Food Technologists is pretty much the singular entity for food technology industry group guidance. For pharma, there is a parallel universe and there are multiple industry groups, ISPE, PDA, USP, etc. Medical device is another parallel universe, with AAMI, ISO, and USP.

Similarly, the regulators have different branches under the same roof, and each covers its own product classes.

U.S. Food and Drug Administration

• Food-Human Foods Program
• Medical Device-Center for Devices and Radiological Health (CDRH)
• Drugs
  • Center for Drug Evaluation and Research (CDER)
  • Center for Biologics Evaluation and Research (CBER)

They all have GMP, but it's not exactly the same between those branches. So, our standards borrow from each other, and the people who are here doing the work make their own interpretations. At times, they can be different. They're not hugely different: for example, with GMP, I think most everyone agrees on what good manufacturing practices are, but how we execute in med device, in biopharma, and even APIs is slightly different.

That leads us to interchangeability. ‘How to prove interchangeability’ has not been a priority because we've been getting our processes evaluated and validated to license and market, but the industry's maturing. As recently as 10 years ago, cost of goods wasn't really in our lexicon. Now it is, right? Interchangeability, finding cost-effective equivalent equipment, is an obvious piece of the COGS puzzle.

I've done many change controls in my career as a process engineer, engineering manager, director, and now as a consultant, and these are not slam dunks. COVID changed the world in a lot of ways, including when you can't buy something. We might have been a little more liberal in our review of a change control when we could not obtain the validated component to make the drug. We still did our best then with what we had, “literately,” in our hands to provide a safe drug.

Can we use these pandemic experiences to demonstrate where we can apply interchangeability?

Vogel: Can we say a silicone tube is suitable because it's platinum-cured silicone? But I think the old adage that says "you need well-built, scientific, and documented proof of equivalency before it can be used" applies here.

We're talking a lot about extractables and leachables, but how often do you see failures caused by subtle physical difference like stiffness or port geometry that would not be captured in standard specs?

Vogel: Well, they are captured in standards. I work on the ASME Bioprocessing Equipment (BPE) Standard, and you need to show that it is equivalent. Let's use flow as an example. Whether it's a single-use or a multi-use valve, if I change out a valve, I'm going to have a different CV or a different flow dynamic through that valve. I need to show in my change control that the process isn't affected or it’s affected in a positive way. If the valve has a restriction or something that changes my process dynamics, then I need to do testing to justify that.

I think this is where the scientific community may have gone too far in focusing on the E&L. We should also focus on the physical/mechanical properties and other things that matter.

At The BioProcess Institute, we're doing a lot of work on particulate generation in tubing. That's a physical thing. It's not extractables. You have these particles come off, and they can be large. Depending on the tubing, pump, and application, the tube can actually fail and rupture during use from the erosion, and your shoes are going to get wet!

Every type of tube we test generates particles that aren't just sub-visible – they're visible and are up to a few millimeters in length, and it can make a snow globe in your process.

Some pump and tubing types will make much less than others, and other things come into play. Was it gamma-irradiated? Was it autoclaved? The physical parameters of the tubing are affected by what we do to it — whether it's pretreatment, autoclaving, irradiation, or, if it's run in a pump, the RPM, etc.

Do you believe that these evolving standards address those issues effectively? Do you think we're behind on that?

Vogel: We're never going to catch up, but this is the dilemma. The engineers want detailed specs on everything. I'm sorry, you're going to have to earn your pay, make your own assessment, and get the data. You can't just get the certificate from the vendor and say, "See, they said it does this, therefore I'm OK."

I've been involved with too many inspections where the regulatory agencies say, "Great. You bought the best, you bought the gold-plated, but do you know it works?" Too many times, the line engineer thinks it's monopoly money or something, and they'll buy a piece of junk because the salesperson said, "This is the best thing since sliced bread." But did you test it on your process?

There's no standard for frozen bag integrity testing. Companies make up their own drop tests. Some are dropping from 3 meters; some might drop from 30 centimeters. Does that leave drug makers even more in the dark about interchangeability for things like cryobags?

Vogel: That's a great example. Ultimately, it's up to the drug maker to look at their process and simulate whatever they're doing. Every process needs to be defined. The process is king or queen. Everything we do – whatever that piece of equipment is – supports the process. We then employ testing methods from the packaging and transportation industries to simulate our uses.

I can't be more passionate about this. You, as the engineer, should give it the best treatment. If it needs to be gold-plated, then damn it, make it gold-plated. If it needs to be packed in bubble wrap, do that, so the process parameters are met.

In the case of cryopreservation, we know the bag is more brittle — it is physics! Even Nalgene bottles are more brittle at those temperatures. Again, it is materials and physics. So, you need the proper apparatus to support it when you move it.

ASTM E3051 was updated in 2025. What was the driver for that update? Did it tighten any of the rules for verifying systems before use?

Vogel: We try to keep it current. To my knowledge, there wasn't any significant driver other than to clean it up with current expectations. And I think that's good. That's the way it should be, just like SOPs inside companies. You should get a fresh set of eyes on them to determine whether they still make sense, update them to the current standards and regulations, and verify that they have not become obsolete.

On USP <665>, do you think that the industry is ready for the May 1 enactment date?

Vogel: We've been ready. But I think the suppliers, and especially those for secondary components like seals and gaskets, are not.

It's important to note that, simultaneously, biocompatibility requirements have changed. For thermoplastics, it's easy — do extractables testing!

But on thermal elastomers — things like silicone, EPDM, Viton, things that are not as sexy as our single-use bags — they're still figuring out what to do.

I think we've done a good job to give guidance in the upcoming 2026 Edition of the ASME BPE Standard. You shall continue with the cytotoxicity elution test described in USP <87> and its counterpart, ISO 10993-5. That's the first line. If you don't have that, don't even bother coming to this market. Today, those people should also have USP Chapter <665>.

Now, the problem is, if I take those elastomers, which are essentially rubbers, and conduct extractables testing, their chemistry and molecular structure will be affected differently than thermoplastics. So now what do I do? This is where we are in that Twilight Zone middle ground. ASME BPE has a task group looking into this right now and we plan to have our best guidance for the 2028 standard. Until then, the engineer/scientist on both sides, suppliers, and end users will have to earn their pay and perform the technical/risk evaluations, utilizing the available standards and science to provide safe and effective drugs. The patients are depending on us to do this.

About The Expert:

James Dean Vogel has more than 42 years of experience in the biopharmaceutical, food, and cosmetic industries, including expertise in facility design, operations management, fit-for-use testing, performance and exposure testing, bioprocess engineering, and biopharmaceutical manufacturing. He is an adjunct professor and currently serves as director of the University of Rhode Island’s Minor in Biochemical Engineering program and as the leader of its Introduction to Biopharmaceutical Manufacturing program. He is a member of volunteer industry organizations, including, ASME’s Bioprocess Equipment (BPE) Standard Committee, ASME BPE Sealing Components Subcommittee, NHAAD’s Hose Safety Institute Advisory Council, ASTM, BPSA, PDA, and ISPE. He is a past member of ISA, IFT, and AAMI. He is a licensed professional engineer in New Jersey. He has a Master of Engineering in chemical engineering from Manhattan College and a Bachelor of Science in biochemical engineering from Rutgers University.