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Biopharmaceutical manufacturers face many bioprocessing concerns including safety, flexibility, maintenance, capacity, capital investment, and process costs. Disposable products can reduce some of the burden.
Single-use disposable technology - from tubing to tank liners - provides a reliable alternative to traditional stainless steel and other reusable systems. In an industry where speed to market is a palpable force, the savings in time and money have compelled many biopharmaceutical manufacturing companies to design disposable systems into their new facilities or replace existing components with single-use alternatives.
BioPharm International spoke with three suppliers - Pall Corporation, Entegris Inc., and Colder Products Company - about what they're doing to help biopharmaceutical companies make the transition to disposable and cleanable technology and where they see these industry sectors headed.
As a leader in producing reusable and disposable chromatography and filtration products for the biopharmaceutical industry, Pall Corporation (East Hills, NY) has seen how biopharmaceutical manufacturing has changed over the years.
"A major shift is taking place in the way the biopharmaceutical industry manufactures drugs," says Holly Haughney, who is vice president of biopharmaceuticals marketing at Pall and responsible for direct flow filtration products including disposable systems. "For production of clinical, pilot, and production batches up to 1,000 L and more, stainless steel production equipment, long the industry standard, is being replaced by single-use disposable products and systems." There is still a place in the industry for stainless steel in large-scale processes, says Haughney, but the shift away from stainless is real.
Table 1. Approximate set-up time required for cartridge filter in stainless steel housing compared with a presterilized, single-use capsule filter
"Disposable capsule filters have been in the marketplace for at least 25 years," says Haughney. "But recently we've seen a much greater use of disposable systems, as larger and larger single-use capsules and peripheral equipment are available." In the past, applications would call for a single-stage disposable capsule. Now, the trend is for larger, single-use capsule systems with filters manifolded together.
Use it once and throw it away. "The need for more and more rigorous documentation on cleaning validation has impacted this market," says Haughney. "With a stainless steel system, it is necessary to validate that the system has been cleaned, which can be difficult to prove. A disposable or single-use system is used once, so there is no need to clean it."
The convenience of disposable systems is a significant advantage for biopharmaceutical companies. Disposable systems do not need to be assembled and sterilized for use or dismantled and cleaned between batches. Less time spent validating equipment means faster production and increased speed to market, two critical concerns for fiercely competitive biotech companies.
These systems can be supplied gamma irradiated, so they're ready to be used right out of the box. And because they're preassembled, an operator can basically plug and play. "Take it out of the box, and it's ready to go," says Haughney. "That saves quite a bit of process time and can streamline process scheduling."
Eliminating the assembly, steaming, and cleaning required with stainless steel systems can also reduce record maintenance.
Using a fully disposable system can eliminate the need to develop a cleaning protocol and conduct a cleaning validation study typically required for a new system, adds Haughney. "And because the system is contained for reduced operator exposure, it provides safety, particularly with cytotoxic drugs, and simplifies training and protocols," she says.
From preclinical to commercial production. "This market is driven by speed," says Haughney. "Speed to market, speed for getting products validated, speed in production. When biopharmaceutical companies need to make clinical batches, or batches during the early phases of development, instead of having to build a stainless steel hard-piped system they may only be using for a short duration on a specific product, a single-use system can be used. It's helped them make their product quickly without a great capital investment and provides the flexibility those companies need at the early stages of development."
Table 2. Time required to make aseptic connections with laminar flow hood, tubing welder, and Pall Kleenpak connector
Single-use capsule filters can also be used in existing production applications where a conversion to a disposable system is desired. "The latest polypropylene disposable capsule designs use the same cartridge filters that are used in stainless steel housings," says Haughney. "Because the filter materials are the same, the validation requirements for conversion from a cartridge filter in a stainless steel housing to a single-use capsule filter are simplified. The designs on the market make it very easy to convert because the materials of construction are essentially the same.
Making sterile connections. Pall has developed a single-use device - the Kleenpak connector - for making aseptic connections between flexible tubing in uncontrolled environments.
These connections are typically made with a tubing welder or under a laminar flow hood. A laminar flow HEPA-filtered air hood creates laminar air flow to ensure that particles do not come into direct contact with the sterile components while a connection is being made. A tubing welder uses wafers or blades to thermally weld two pieces of tubing together.
Both options require a capital investment. Although use of these techniques is widespread, Haughney says there are limitations. For example, the connection must be made where the equipment is located. In a cramped environment, this can be difficult.
Traditional connecting methods can also be time-consuming to set up. Aseptic connecting devices such as Pall's Kleenpak connector are designed to shorten the time it takes to create aseptic connections (see Tables 1 and 2).
"It is also necessary to consider the validation and maintenance requirements for laminar flow hoods and tubing welders," adds Haughney. "With the Kleenpak connector, all you need is an operator to put together a male and a female device in seconds. No additional equipment is required, so the time and any risk associated with [a laminar flow hood or tubing welder] are eliminated."
Transferring sterile fluids is a source of significant cost in biopharmaceutical manufacturing. This process is also time-consuming and can carry the risk of cross-contamination. The traditional equipment involved in fluid transfer - product piping, stainless steel vessels, routing manifolds, and valves - needs to be cleaned and sterilized, a timely, costly, and sometimes risky process.
Table 3. Estimated cost savings achievable by using Colder Products' Steam-Thru Connection device compared with conventional connections
Entegris Inc. (Chaska, MN) is developing products designed to help its customers safely transfer these critical materials and dramatically reduce cleaning requirements. A long-time leader in the semiconductor industry, Entegris brings to the biomanufacturing arena expertise in fluid handling and fluoropolymer research and development.
Mark Cole is vice president of marketing at Entegris. "We're embarking on a lot of research and development in solving those issues we're finding in the [biopharmaceutical] industry," says Cole. In addition to its research into fluoropolymers, Entegris has developed a dedicated marketing group focused on the biopharmaceutical industry and has recently acquired Electrol Specialties Company, a leader in clean-in-place (CIP) technology.
"This [acquisition] has provided us a very nice opportunity to create some synergy between the ferrous alloy materials traditionally used [in bioprocessing] and some of the new fluoropolymer products we've developed," says Cole.
"Electrol Specialties is a market leader in its ability to design a cleanable system and fabricate it for the end user," he adds. "If you think about the cleanability requirement of a system up front and design that cleanability into it, it makes a huge difference. And it goes right to the bottom line for these [manufacturers] when they can clean it quickly and get right back into production."
The search for nonreactive surfaces. "I'm hearing a lot about corrosion, especially reactive surfaces," says Cole. "When the surfaces on the insides of valves, fittings, tubing, pipe - and especially inside tanks and vessels where there's a much longer residence time - start to change, [manufacturers] have a problem."
When that happens, manufacturers are no longer satisfying the requirements of manufacturing that product as it was originally certified. Cole believes this is one reason people are researching the use of exotic metals.
Although exotic metals - such as Monel, Hastalloy, and AL6XN - have been shown to be less corrodible than stainless steel, corrosion is still possible.
"They're still reactive," says Cole of these products. "Compared to something like PFA Teflon or PTFE Teflon, they're orders of magnitude more reactive."
Affordable one-time use. The search for a nonreactive surface has led some companies to adopt disposable processing systems or highly cleanable solutions made of nonreactive fluoropolymer materials.
"One of our core competencies has clearly been in polymers and fluoropolymers, and a lot of affordable one-time use activities employ those kind of materials rather than ferrous alloys."
Advances in materials integrity management. "Within the past year we have developed steam-in-place (SIP) and clean-in-place (CIP) compatible fluid handling systems - including valves, fittings, and tubing - and more recently a sheet lining product for vessels," says Cole. The product protects the surface of large (2,000 L or larger) vessels with a 2- to 3-mm–thick lining of fluoropolymer (PFA or PTFE).
The material provides a completely inert, totally nonreactive surface. It has excellent cleanability compared to ferrous alloys or exotic metals. "This is a big technological breakthrough for us," says Cole. "We're seeing a lot of interest in it because of the residence time in vessels. It's a big deal."
Regulatory challenges and risk aversion. "New technology gets adopted very slowly in this industry compared to the microelectronics industry because of the risk aversion among end users," says Cole. "[In the microelectronics industry] you can make a transition from stainless to a more inert material like PTFE or PFA. There's no hesitancy. If you can see an economic benefit, you do it.
"I think the big fear that a lot of [biopharmaceutical companies] have is not that they're going to have a problem with this new system, but they know that something's going to be found somewhere else in their system that's going to be a problem. And they just don't want to raise any red flags. There's huge risk aversion to making those kinds of changes for that reason."
Connections - between pipes, valves, fittings, tanks, and vessels - are critical in biopharmaceutical applications. Biopharmaceutical companies are focused on the safety and performance of major capital equipment used for bioprocessing. However, capital equipment is only as safe and effective as the connection that feeds it. The use of an effective connection device can significantly improve the speed, safety, and economics of fluid connections.
Connections are used throughout biopharmaceutical drug development to link key processes together. The most critical connection takes place between a bioreactor and the media bag. Here a connection is used to add media to a bioreactor or remove product from it. This is the most critical connection and also the most difficult to establish because a bioreactor is an immobile piece of capital equipment with specific size and sterilization requirements.
How it works. Carolyn Franceschi is the medical business unit manager at Colder Products Company (St. Paul, MN). Franceschi describes how Colder Products' Steam-Thru Connection (STC) device can be used to reduce validation concerns related to the aseptic connection process.
"An STC can be steam-sterilized while situated between the media bag and the bioreactor," says Franceschi. Steam flows from the bioreactor through the connection to sterilize the device. It then exits through a "steam trap" to ensure that remnant microorganisms do not become trapped within the device. Once the tear-away sleeve is removed and the device is actuated, the STC transforms from a valve into a connection, allowing fluids to pass from the media bag into the bioreactor and vice versa.
In traditional connection applications, the media bag is coupled to the bioreactor with a reusable connection device that is sterilized before connection. Once the device is sterilized, a laminar flow hood is used to prevent contamination during the connection process. This process can be inefficient and costly.
Reducing contamination risk. Franceschi explains that many SIP processes are vulnerable to contamination because the steam used to sterilize the connection is left to dissipate within the device, creating "dead legs" following sterilization.
Dead legs can be eliminated with the Colder device by providing an escape route for remnant steam. This reduces the chances of contamination and minimizes validation concerns.
No capital investment. Biopharmaceutical companies have realized cost savings by using STCs (such as Colder Products' device) because they can be steamed in place without the need for additional equipment or connection points (see Table 3). Colder's device uses a valve that separates the flow path from the steam path once sterilization is complete. This type of steam sterilization creates an aseptic path through which fluids can immediately flow.
"For a blockbuster drug, millions of dollars can be lost during the time a product is not on the market," says Pall's Haughney. "Single-use systems can speed processing time and reduce time required for validation."
Saving money, saving time. Streamlining the aseptic connection process can save time and money, adds Colder's Franceschi. "Disposable connection devices that serve the dual function of a steam-in-place valve and coupler provide significant cost savings over traditional reusable connection devices by reducing the amount of time required to make a sterile connection."
"Single-use products can dramatically improve the speed, safety, and economics of drug development," says Haughney, "whether used individually to make sterile connections, or bundled together to provide a fully integrated filtration system."
Purchasing prebundled disposable products can actually reduce the number of connections requiring sterilization in biopharmaceutical applications, adds Franceschi. "Bioprocessing applications require a multitude of aseptic connections. The use of disposable prebundled systems can significantly reduce this number," she says.
Reducing risk. "Cleaning and cleaning validation are required every time a hard-piped system is used in a biopharmaceutical application," says Franceschi. "These labor-intensive processes introduce opportunities for both contamination and noncompliance with FDA regulations."
The bottom line. Reducing risk, cutting costs, and saving time are critical issues for today's biopharmaceutical manufacturers. Entegris's Cole points to other concerns that demand further research into single-use technology and stainless steel alternatives, including increasing niche applications for nonmetallic systems for use with metal-sensitive proteins. "Until now, [those proteins] have really been sitting on the shelf," he says.
Through further research and development into emerging technologies - such as disposable technology - and continued cooperation between suppliers and end users, the complex challenges of bioprocessing - from cutting costs to controlling contamination - can be met. BPI