Outlooks on Standardization

The Friday workshop of the 2011 BPI Conference in November may have been titled “Industrialization of Single-Use Manufacturing Technologies,” but in the discussion afterward, the mainly end-user audience zeroed in on an on-going debate in single-use implementation: standardization. Comments and questions echoed the current opinions, most of which were well known to the all-supplier panel and others present. To follow up on this discussion, I spoke with members of that panel because — as one expert put it —“there is a huge need to compare apples and oranges to see where everyone is. Everyone is asking for this, primarily end users, but there is a fair amount of equipment companies as well.” That’s from James Vogel, founder of the BioProcess Institute and member of BPSA, ISPE, and ASME BPE, and although not on the workshop panel came highly recommended for inclusion here.

The Stance on Standardization

The standardization debate has gone on for some time with issues familiar to all industry stakeholders. “The market has spoken, we, the vendors, have listened, and consolidated efforts have moved beyond the initial intellectual property and proprietary design hurdles,” says Jeff Craig (ATMI LifeSciences). “You’re seeing an effort by the suppliers of the technology to provide definitions in as much clarity as they can for chemical and physical standardization.” However, he goes on, “let’s be honest: You’re not going to get competitors sharing their engineering specifications with each other so that they can be interchangeable. That is the same as in every industry.”

Workshop Panel

Besides disagreements over definitions (see sidebar “What’s in a Word?” next page), there is a fundamental discrepancy between end users and suppliers about the extent to which standardization can harm or benefit productivity. Ultimately, the level must include a balance between respecting intellectual property and satisfying end-user needs. But where that balance lies in the spectrum between commoditization and customization is anyone’s guess.

“Some users see benefits in having some degree of standardization so that they can potentially source things from multiple suppliers and have some kind of interchangeability,” says Ian Sellick (Pall Life Sciences). “The counter to that is one of the real benefits of single-use systems, which is the ease of customization. A limited number of standardized solutions may not necessarily optimize what an individual user may need to do.”

“The call for standardization is more often driven by commercial people who don’t necessarily appreciate the finer points of customization,” says Sellick. But not all vendors are willing to supply highly customized systems. “I can see some being quite happy to go along with the standardization path because it means less work from their point of view. We tend to prefer to provide things that are truly optimized for what a user wants to do.” Where there may be room for both is in the earlier uses of disposables such as for buffer storage and other places not directly involved in a process. “If vendor X puts five feet of tubing and vendor Y puts seven feet of tubing, it’s probably not going to make a whole lot of difference to the process. But some areas may be more critical, such as in direct product contact processes to minimize path length and maximize product recovery.”

Vogel says end users want to be able to compare technologies so they can really assess the value that is being brought to them. “This is a very difficult task in most cases. How do you do that? On a technology side, you have to look at capabilities. Then you have to look at the economics. Will it cost the same per batch, per campaign? It’s hard because they are so different to compare. That’s probably the biggest issue. Most companies today are retrofitting. They are not building big plants like they used to.”

Workshop Panel

Kevin Ott, executive director at Bio-Process Systems Alliance
Paul Priebe, director of fluid management technology at Sartorius-Stedim Biotech.
Jeff Craig, global director of business development at ATMI LifeSciences
Fred Mann, program manager of biopharm process solutions at EMD Millipore
Ian Sellick, director of marketing at Pall Life Sciences

But standardization may not be all bad for the supplier base. “For us, standardization has its own appeal, and we believe there are benefits,” says Paul Priebe (Sartorius-Stedim Biotech). As the opposite of customization, standardization would begin to give suppliers scale effects — a mass production of a standard product for many different customers instead of small numbers for only one customer. The obvious benefits would be in simplicity, scaling, better quality control, security of supply, and so on. “That directly benefits our end users,” says Priebe. His company’s standard products are growing faster than its custom product sales. “We are seeing a transition, and people are embracing this idea of standardization.”

Customers can get off-the-shelf delivery of standard products so they don’t have the long lead times of built-to-order units. Suppliers can maintain stock to deal with emergency demands.

“Now of course, what that often means is compromise,” says Priebe. “We’ve got to bring up product to the market that has the features that the customers need, but sometimes they need to compromise on their specific needs to allow use of standard product instead of a custom design. A customer wants a bag with three feet of tubing, but our standard has five feet. Extra tubing may not be ideal for them, but in the single-use world it allows them to use standard products.”

“From a supplier standpoint, it is difficult to put the same ‘level’ of engineering effort into designing and ‘validating’ customized products or assemblies than it is if it were preengineered or standard assemblies,” says Fred Mann (EMD Millipore). “End users tend to feel that standard assemblies are reducing their flexibility, but they are likely to have a more rugged and more reliable assembly if it’s standard because it’s able to be subjected to a lot more testing and validation than if it was a custom product. There is a responsibility on the supplier or manufacturer to follow the same engineering practice that they would for a stainless steel systems, so to do risk analysis on the design and use of the system or assembly (FMEA analysis). There is also a need or responsibility for users to do such an analysis as well, because there is a lot more handling with single-use assemblies. It needs to be a partnership; the supplier can do so much, but it needs end users to participate as well.”

Where It Might Make Sense

During discussion with the audience, the panel suggested a distinction between the various areas in which standardization may or may not be realistic. Those included equipment and components (connectors, bags), materials (single-use films); and testing and validation (solutions and extractables/leachables assays). I asked the panel their views on each area.

Equipment: Many suppliers believe that full standardization of equipment will simply not happen. The market is too attracti
ve, and companies that have invested a great amount of R&D innovation time and cost want some exclusivity and return on their investments. “I don’t know that we’ve reached a state in the industry where any supplier or all suppliers are ready to lay down their arms and join together for the benefit of the end users, and commoditization of the marketplace,” says Priebe. “We want to drive innovation, and the drivers toward innovation remain the attractiveness of the marketplace. That’s healthy for the market right now and for end users. There is a certain maturity that needs to come from that, but I don’t think standardization in that definition is the right thing for anyone at this time.”

What’s in a Word?

Industrialization can have different interpretations. “There is a big opportunity for people to take the industrialization term and interpret it to their own means and go running off in a certain direction,” says Priebe. For Jeff Craig, industrialization means high-volume manufacturing instead of process developing; it’s the go-to manufacturing tool that doesn’t have to be proven and reproven. “The supplier base isn’t particularly crazy about the word standardization,” says Ott. “They prefer harmonization. And, as much as suppliers may dislike standardization they shrink at the word commoditization,” he says. Suppliers fear standardization may reach a point it will diminish end-user choice. “Are you going to go to a catalog and pick out your single-use manufacturing platform? That’s how many interpret standardization,” says Ott. “You can go to a restaurant and pick a red or a white to drink with dinner, but you also have a hundred variations within those vintages, all at different price points. Some customization will always be a feature and a benefit of single-use.”

Another interpretation is thinking that the industry is going to move to single use from stainless steel, such that single use will be “de facto technology” in the future. “I don’t think that will be the case,” says Mann. “Single-use systems have some very definite advantages when you are working at small scale and with clinical batches, where you are producing just a few batches of a particular molecule and then want to change to another molecule or if commercial manufacturing only requires small amounts to be produced per year. But for a facility that is making the same drug over and over, a stainless steel facility may be okay, as the cost of cleaning and validation is spread across multiple lots, whether at large or intermediate scale. I think we are going to continue to see hybrid facilities.”

Ott also thinks that the main drivers will be end users. “The customer is king….so whatever they want they are going to demand from the supplier base,” he says. “It’s what going to make the highest quality product that employs ease of use and cost effectiveness. It’s an on-going dialogue between supplier and end-user. The question is, when does single use reach such a critical mass in end user facilities such that these ‘harmonization’ issues need to be addressed? At what point do you poke the end-user sleeping giant and he wakes up and says, ‘Wait, we’re over the hump here— our plant is predominantly plastic-oriented and we’re paying too much for custom systems.’ I’m not sure when that point will be reached.”

Having emerged only about five years ago, SUTs now may be on the verge of wide-scale adoption. “The pharmaceutical business model will be going through a paradigm shift over the next decade,” says Ott. “They will be changing the way they do business. I am speaking of everything here — from R&D through manufacturing, supply chain efficiencies and delivery of medicines to patients — at accessible price points. One element of that change is fast, sterile, reliable, and efficient therapy and vaccine production. So disposable,flexible, ease-of-campaign-switchover platforms are what they will want and need, and the SUT supplier base will have to poised to meet those needs — and price will be a factor there, too.”

Working Groups

The extent of work under way in standardization issues is far beyond the scope of this article. Several industry organizations are currently considering the issues presented here, including BPSA, the standards organization ASME, PDA, and ISO. ISPE is preparing to launch a baseline guide effort for single use. Information about the each organization can be found on their respective websites.

Much of the focus on equipment standardization so far has to do with connections between two different equipment brands. “Those who have been around the bioprocess industry a long time remember the days when the BPE standard for a sanitary flange was established, about 10–20 years or so,” says Priebe. “In those days, there were competing companies, and things didn’t always fit together and sometimes you had leaks. The connection of two different pieces of single-use process equipment seems to be what many people focus on for standardization. For the proprietary connections, I don’t think the industry is ready for that. Many suppliers take the position of ‘I’m all for standardization as long as the industry standardizes on my solution.’”

Whether the industry will reach standardization depends on the types of connectors: “critical” (or sterile to sterile) or “noncritical” (nonsterile). “In some areas, there are some almost de facto standards emerging,” says Mann. “For noncritical connections, people use the plastic equivalent to tri-clamp [BPE] fittings, which became the standard in stainless steel connections, or connectors from Colder, which are used by many suppliers because they are convenient. When we move to sterile to sterile connectors, then we see different products and solutions from vendors and they have pluses and minuses, some offer more convenience than others but may not offer the same degree of robustness or sterility assurance. People are continuing to innovate and trying to improve such connectors, but if you standardize too early the danger is you may suppress that innovation.”

Some users are also seeking standardization in common process container sizes (e.g., 20-L, 50-L, and 500-L bags) and possibly the shapes of those bags. They want flexibility to select from different suppliers, bags that would fit in the same bins or plastic containers currently in use. Currently, if you have a 50-L bag from one supplier with different dimensions from those of another supplier, then you need another container to hold it.

Standardization in this area may be possible, but it will take some work. “I think it helps if users can have a collective voice because that will certainly help bring both sides together,” says Mann. Here again, however, if standardization is completed too quickly, it will not be beneficial to productivity. “In some ways that is the beauty of it; It can’t be standard because it’s open platform,” says Vogel. “Designs are developing so fast. You can’t come up with a standard instantly; you need some time to flesh out what it’s going to be. When the technology changes, standards can be obsolete, and the technology could change by the time the standard gets out there.”

Materials: Single-use materials may be an area in which standardization could work. For example, when ASME established its bioprocessing equipment (BPE) standards for the tri-clamp sanitary flange, it pertained only to stainless steel, not plastic sanitary connectors. “BPSA has asked ASME to look at the sanitary connector because all of the problems that existed with the tri-clamp [BPE] sanitary flange in stainless steel are happening today in plastics,” said Pri
ebe. The material of construction is one of the biggest parts of the standard. People think there’s a standard, but there is not, and it could lead to some issues. Here, standards would bring value for connectors that are not IP protected or standardized yet. So there is room for some significant contribution from standardization. In fact. the supplier base said as much and has asked ASME to engage on the topic.”

The code 7 filter housing is one example of a de facto standard. “End users of filters believe that there is a standard for code 7 filter housing. But in fact there is no standard, but the execution of code 7 housings is generally consistent enough for interchangeability,” says Priebe. “Everyone uses the same type of filter fittings in the industry,” says Sellick. “But that wasn’t arrived at because a regulator said we had to; it was arrived simply by a consensus opinion of what was best. And without an intellectual property barrier, everybody adopted the same standard.”

Currently, the same is not true about single-use film. Several suppliers make their own plastic film for their disposable systems. Even if the industry decided to settle on polyethylene film as the fluid contact layer, for example, the properties of that film and the way it behaves under required testing may differ unless it was all obtained from one supplier and source and handled in the same way. “Obviously, bag manufacturers are not going to give away their layer formulas, how they sort their film, what the wet layer is, how many layers, and so on,” says Kevin Ott, (BPSA, and workshop moderator).

The industry has yet to agree on the one “ideal” film or polymer with desired mechanical properties, low extractables, biocompatibility, and nonspecific binding to proteins or cells. Most materials are multilayer films with their inner contact layers designed for low extractables and good biocompatibility. But they may not be physically strong enough to withstand bag handling or offer good properties for heat sealing or bonding. “That is what people are working with today,” says Mann. “That’s the point suppliers are making: It’s still fairly early in the industry and we are still trying to find the best film.”

“Film standardization and extractable analysis are tough ones,” says Priebe. “In some way, there’s an ‘As long as it’s my protocol, then I’m happy’ sentiment. But there is also a bit of protection from the supplier side. Standardization of films or the characterization of them certainly brings us into the direction of commoditization. Although most suppliers seek to differentiate on something other than the specifics of their films. It’s more about the total solution, the support, and quality aspects of the product. The reality is that there’s a pretty big number of suppliers, and that is a strong argument against [standardization] ever happening.”

Testing: Particulate testing and system integrity testing are two areas that have been under some discussion among supplier and end user organizations. However, the biggest concern — certainly where a lot of discussion has been centered — is about extractables and leachables. Having added end users to its organization, BPSA is one of the organizations taking the lead on this topic, at which ASME is starting to look as well. “Extractables and leachables are probably number one in people’s minds,” says Sellick. “But ultimately, the responsibility is with end users to determine the suitability for their use of a single-use system and the components in it. Regulatory authorities look to end users to make sure they have done all their homework in risk assessment. It’s an opportunity for users to partner with vendors in generating information.”

Other parts of the industry may provide a good starting point for determining what information may be needed as a baseline. There may be a great deal to learn, for example, from requirements for testing extractables from plastic vials and stoppers and filter cartridges, which have been used for some time, or blood bags, blood collection and storage systems, and medical plastic bags with tubing and filters attached that directly contact patients.

“Honestly class VI is just scratching the surface of where this is going to end up,” says Craig. “That was the requirement two years ago. Now as suppliers are moving to high-volume manufacturing, they are digging much deeper into chemical analysis of film as it relates to not only the patient, but to their products.”

The Center for Devices and Radiological Health (CDRH) may help. In June 2011, the Center issued draft guidances in classification of products as drugs and devices and the interpretation of chemical action. “They are trying to at least get the language to people,” says Vogel. “We’re not talking about nanogram extractables. Let us start talking about the big picture and work our way down. These are two draft guidances that from my perspective are trying to get everyone on the same page. But again, you can’t do this instantly. To quote one of my bosses, ‘GMP isn’t a light switch, you don’t just turn it on.’ It really has to be a philosophy, and has to be worked on, and people need training if they are really to embrace it. I think the same thing with this, it’s going to take a little bit of time.”

Unlike equipment and materials, most experts agree standardization of testing methods and procedures can happen, but there is still a general disagreement on how close we are to achieving that. “It would certainly benefit users, and personally I suggest it would benefit suppliers as well if there is standardization in terms of the particular assays, test methods, and test solutions,” says Mann. “Users can compare apples to apples between different products and also in a way suppliers can compare their products or products they have in development.”

Experts agree that the industry is getting closer in testing harmonization, but there is much to be done. “BPSA has done a very good job at laying it out, but I still think we are not where we need to be because we can’t make comparisons. I’ve evaluated many extractables and leachables reports, and it’s very difficult to compare brand X and brand Y. Invariably companies have different labs, their conditions are different, or something else is different, so you can’t do it.

Vogel points to a general lack of understanding regarding material science and what people want materials to do. “We can’t change the material, but we need to understand materials from the standpoint of application and interaction with a process. Suppliers do extractables testing, but they can’t even answer some basic questions of chemical compatibility. Everything interacts to some degree. For example, there are assumptions that stainless steel is an inert component, but it actuality it does interact (causing rouge in those systems). Where single use starts to get ‘confusing’ or intricate is how much is acceptable and complies with ICH Q9.”

The Pace of Progress

Experts agree that some standardization, with or without “interchangeability” will eventually come to this industry, much as it has for other industries. It will take baby steps so that as not to hinder or impede innovation. And some effort will need to be made to ensure that it doesn’t happen so prematurely that the pace of technology quickly renders it obsolete. The needs are there, even though other concerns about single use are ranked more important. Craig says his customers ask for standardization “daily” but that they are “realistic and understanding” about the pace of progress. “They want to see continued innovation so that they can process with the same or better control and security, sterility and everything else that they would have had they made a hard
pipe decision” says Priebe. “They don’t want to look back in five years to find that they made mistakes.”.

About the Author

Author Details
Maribel Rios is managing editor of BioProcess International; [email protected].