Efforts Toward the Harmonization of Single-Use Standards

During the 2013 BioProcess Conference and Exhibition, in Boston, MA, BPI held a town hall on single-use standardizations and best practices. The purpose was to update attendees on the current status of standardization and harmonization of single-use systems from the perspectives of a number of user groups and discuss the approach of each organization to such efforts. James D. Vogel, founder and director of The BioProcess Institute, moderated a panel of representatives from the Parenteral Drug Association (PDA), the International Society for Pharmaceutical Engineering (ISPE), American Society of Mechanical Engineers-BioProcessing Equipment (ASME-BPE), the BioPhorum Operations Group (BPOG), and the Bio-Process Systems Alliance (BPSA). Here are the highlights of that forum.



An Overview

Vogel started by addressing the fundamental questions: “Where is single-use right now? Where is the collective thinking, and where do we all want this to go? What we do know today is that it's a very competitive industry. Titers are up, batch sizes are down, and processes are closed. A lot of that has been a direct result of the impact of single-use systems.

“Sometimes we lose perspective of what single-use has contributed to the bioprocess industry. For example, recent reports shows that 92% of filter cartridges are now disposable. In fact, the majority of processing operations can be conducted with single-use systems. Consequently, the real value is that contamination risk is almost eliminated — both from the production environment and from cross-product contamination. In addition, a lot of work has been done in understanding leachables and extractables. And the issue of supply chain is becoming a major concern, whereas maybe a few years ago it wasn't as prevalent. Now it's definitely on the table.

“Another major challenge has been the quest for standardization. But what is standardization, and what does it mean to each of us? It has a different meaning to different people. To quote Doug Neugold (from ATMI) at the BPSA summit: ‘Standardization can reduce qualification and validation costs. It can help focus efforts into value-added areas. It can enable growth, industrialization, and globalization.’ I think a lot of people share his view.

“Several organizations can write standards, but how do we go about this? Those organizations represent us, the bioprocess industry. We're all involved with this. We have an ‘alphabet soup’ of organizations looking at what they can do. In the calls preceding today's presentation, we have found that there is some overlap, and there are opportunities for us to work together.

“Another question is, How much can each group do [in the work toward single-use standardization]? Is it right that one group does everything, or is there an opportunity to harmonize, synergize, and come up with a way that we can all look at the issues? Understandably, there is some competition with that, but there's also a limited pool of resources to get it done.

“Many users of single-use systems are saying they need connector compatibility, material standardization, and standard dimensions and configurations. That is one aspect of standardization. But what are the key organizations that end users expect to set such standards? That question has caused some confusion, and that is what the groups will discuss (below). The main concerns currently have to do with design, regulatory issues, component control, and — of course — leachables and extractables, which is one of the focuses on the panel. But the question is whether the directives should be from regulators, suppliers, or end-users. This is the ‘chaos’: Who decides what becomes the standard?”

ASTM

Robert Steininger (senior vice president of manufacturing at Acceleron Pharmaceuticals) was scheduled to attend the panel but could not. Vogel presented ASTM's perspective in his place.

“ASTM is a large organization that has been around for 110 years. It has 30,000 technical experts and has standards that are credited in over 100 different industries. The E55 committee is a branch that works on pharmaceuticals and practices related to them. In 2003, ASTM and ISPE worked on expanding process analytical technologies (PAT) to all areas of manufacture. The E55 has 175 members around the world, including those from government and the bioprocess industry.

“A number of standards are currently in progress. The biotech subcommittee is looking at viral removal and inactivation. It also is working on issues related to continuous processes, and single-use technology standards. Specifically, the E2097 document [www.astm.org/Standards/E2097.htm] provides guidance for determining the impact of extractables from nonmetallic materials and the safety of biotechnology products. The committee is currently working to update that document.

“The goal for the E2097 standard is really to ‘describe tests to qualify materials with respect to any extractable substances so as to prevent unintentional introduction of a potential source of objectionable substances.’ The committee is working on achieving consistency within the industry by determining a path by which suppliers, users, and other industry stakeholders can work toward those objectives.”

PDA

Bob Repetto is a senior director of external affairs at Pfizer and chairman of the PDA's global taskforce for single-use systems. He reviewed PDA's work in establishing workshops and best-practices guidances.

“PDA develops and publishes technical reports, both for traditional technologies such as cleaning validation and relatively newer technologies such as single-use systems. The organization has also been actively commenting on US Food and Drug Administration proposals. So connecting people, science, and regulation is really our mission. Another part of that mission is enabling the single-use systems market. To that end, PDA has formed a task force — consisting of 20–25 experts and including suppliers, regulators, and end users from Europe and the United States — to work on a technical report on single-use technologies. The target audience is not only bioprocess companies, but also manufacturers of vaccines, gene therapies, and emerging cell therapies.

“Completing a PDA consensus document such as a technical report is a difficult task. But because of that challenge, those reports are valuable and useful. Technical reports are peer-reviewed, and we've had two US and two EU workshops where the materials have been presented publicly for discussion, followed by communications. We've modified and amended the report as a result of the comments back and participation from those who have said that they want to participate.

“When available, the report will be reviewed through the PDA advisory board and regulators who represent a global perspective for best practices — not necessarily a prescriptive practice, but a best practice in the opinion of the technical report that will enable the technology. We have found that a report written by end users, suppliers, and regulatory agencies opens up discussions and provides a good compromise among all three parties.

“Those discussion have been most valuable to the task force in my opinion. Getting everything down on paper is a challenge. Documents start by introducing the manufacturing strategy for single-use technology. It consists of the questions, business drivers, and other considerations that are important for an organization. ‘Why are you doing single-use technology? What's the value for your organization? How are you going to qualify it? What technology are you using? What are the details of that?’ This section is followed by a discussion about implementation. We try to provide best practices and ideas about how to go about it, and those ideas become the chapters of the report.

“For example, technology and system integration are points to consider when conducting a feasibility study. Questions include, What are those important aspects of the technology to take into account? How do you compare multiuse-system operations to what you might be doing with a single-use system? What are the complexities of the supply chain with single-use and multiuse systems? The report also will offer some guidance about important business drivers for implementing single-use systems, including financial benefits — because it's going to be less expensive to operate — and improved sterility assurance. Other business drivers include faster progress to market, easier building of facilities, and less time to switch over between products. Other considerations are costs for implementing single-use systems in cases where you are essentially outsourcing some quality aspects of the single-use systems. What do you have to do to maintain that level of compliance for your organization?

“Another section in the report discusses qualification. The document includes a section on leachables and extractables, for example. In this area, PDA is advocating a risk-based approach. We will not be prescriptive. We will not be telling you what solvent you should be using. We'll outline what the industry is using. We'll also use the BPSA decision tree as a best practice for how you would consider to go about designing some studies for leachables and extractables. We will be leveraging that work with BPSA. So there is some harmonization already going on between the documents.

“We also support the BPOG initiative to come up with a standard that then could be executed identically among suppliers. And I think that would be an enabling aspect as well.

“So PDA technical reports provide flexible guidance and points to consider. We encourage asking the right questions to determine whether single-use technologies would be right for your situation and try to give you information so that you could make thoughtful decisions. We provide best practices so that end users can develop a partnership with suppliers and regulators. In particular, PDA task force members are recognized leaders in the industry. They also are members of other organizations, so we have a good representation.

“It's like any other unfunded volunteer effort. It takes time and diligence and perseverance from everybody to come up with the best work in their spare time after hours.”

ISPE

Pietro Perrone, Mobius single-use systems engineer at EMD Millipore, presented the work of ISPE. He chairs the organization's Disposables Community of Practice (CoP).

“ISPE's activity relative to single-use technology primarily has been done through its Disposables CoP. The ISPE core purpose has been to manage knowledge. We as a group seek to find and share information that can be used in manufacturing — typically aimed at industry but also for our members. Most of our members work in the biopharmaceutical industry. The Disposables CoP is a group that started in 2007 and now consists of 1,700 members. We also have a steering committee of 22 members that is split between end-user and supplier companies. So we have a balanced perspective on any documents that we put together. The mission for the Disposables CoP is similar to that of ISPE: collect information and distribute information to wide audiences through knowledge, technical papers, and a discussion database where people can post questions and members for the organization.

“So why is ISPE involved in single-use technology discussions? Some of our members have found that when implementing a new single-use technology there are a lot of details that have to be worked out. They often are surprised at the mountain of details that have to be worked out. Those surprises can set you back, and in a regulated industry those delays can cause production schedules to go out the window.

“ISPE decided to put together a good-practice guide to single-use technology. This guide will help reduce those ‘mountain peaks’ so that you have a better perspective of where you need to go and what you need to do to get there. We'll give you a road map so that you can get through the details easily or at least predictably. And if there are some issues that come up (some surprises undoubtedly could come up), you have a set of tools to help you address those surprises and get yourself back on schedule.

“This good-practice guide is set up into three main categories: quality and regulatory, design, and management. Each category has a number of sections. ISPE members are all volunteers, and each section is assigned to either one individual or a group of individuals to write a draft for a particular section.

“We've made progress on all sections. Some sections have a draft completed. For those who don't have a draft, we have an expanded outline that lays out the framework of what needs to be done, what needs to be covered in that section so that the person writing that section can interact with other sections and prevent duplicate effort. Although some sections do overlap quite a bit, we foresee some shifting of information down the road. After most drafts are completed, ISPE will try to synchronize as many as possible into a complete guide, with a continuous writing style.

“The Disposables CoP also is involved with distributing information that's useful to its membership and/or end-users. For example, knowledge briefs (such as for implementing disposables in a bioreactive facility) are very short technical documents that can be practical in nature. In addition, on our website we can address questions that you may have.

“ISPE is a group of volunteers. we're always looking for people to help out with these tasks. We want to get as wide a perspective as possible to develop this guide. The guide is really aimed at the people who are doing the work. So people who have experience in a pharmaceutical plant can participate in developing this guide. It will help them, and it will help the industry in general.”

ASME

ASME Bioprocessing Equipment (BPE) establishes bioprocess equipment standards. Vogel presented on this work, sitting in for BPE chair Jay Ankers (director of technology at M+W Group) and Michael Zumbrum, (president of Maztech) who chairs the BPE subcommittee on polymers and other metallics.

“ASME has been around since the industrial revolution, when it saw the need for inspection of boilers for safety. The organization writes many codes and are referenced in quite a few legal documents. It includes a delegate program and other forums where it interacts with other countries.

“The BPE's scope was changed in 2012, which is something that not everyone is aware of. The purpose of the BPE standard is to provide requirements for single-use systems and components. This is a tool that you can use when you're working with single-use systems.

“ASME BPE receives inputs from end-users, vendors, and consultants. We have representatives from associations in government as well as the public. Those groups form a consensus standard. The entire process is a little more formal than the ISPE or the PDA process. It requires much more rigor in the voting and approval of what gets through.

“When you look at the outputs, there are requirements and then there's a nonmandatory section. There's a little bit of confusion with that section of the standard. It's part of the process that happens inside one of these standards or organizations. The nonmandatory section is about supporting the standard. In many cases, the nonmandatory sections eventually become part of a standard. In some cases they're removed at a later date because (for whatever reason) the standards committee did not choose to leave it there.

“With regard to single-use systems, we're talking about USP Class VI, lot traceability, shelf life, performance attributes, and definitions to help navigate this. Those are the main parts of the standard. The nonmandatory appendices includes discussions about extractables and leachables and methods and other studies.”

BPOG

Mark Brower (senior research chemical engineer at Merck) spoke on behalf of BPOG.

“BPOG is an end-user group of 21 biopharmaceutical companies, with 600 active individual members. The organizatin, includes 12 active work teams. One is the extractables and leachables team, which was formed in July of 2012.

“Extractables and leachables present a real risk to patient safety. That risk ends up on the shoulders of end-users. So getting together as a group to identify problems and come up with solutions is of key interest. There are no specific FDA guidances to handle extractables and leachables at this time. And not all data packs by vendors are the same. It's very difficult to know how to move forward without such guidances in place. As a group we're hoping to come up with solutions to that problem.

“BPOG is developing a standard for extractable protocols for suppliers. It will cover methods for extractable studies, worst-case scenarios, and what should be included in package details. There's a heavy analytical focus on how to define leachable and extractable components as well, inlcuding for bags, tubing, connectors, and other single-use components.

“Currently, there is a draft undergoing for industry review among 14 companies. There are also one-on- -one feedbacks ongoing with nine selected suppliers. And there was a review of comments in 2013. Taking in all feedback, we plan to revise the draft.”

BPSA

Jerold Martin (vice-president of global scientific affairs at Pall Corporation) presented the perspective of BPSA.

“BPSA started in 2006 as a supplier trade association but has since changed its charter to now include 50 member companies of both suppliers and end-users. We are a company membership rather than an individual membership. BPSA provides networking opportunities for suppliers among each other and with users. We have a legal safe harbor for dialogue among suppliers and provide end-user and supplier forums to discuss and develop best practices specifically for single-use. BPSA focuses only on single-use systems.

“BPSA started out saying that we're at the nascent beginning of single-use. Things were ready to take off about 2006, and we realized that if suppliers went different directions in recommending best practices, then it would be very confusing to end users, and it would be very confusing to regulators. It could also slow down the implementation of single-use technologies. So as we gain a consensus of what the best practices were, the more readily people would be able to adopt single-use technology. And we wanted to do something that wasn't being done by other organizations: specifically hone in on the technical expertise that exists within the supplier base. Separating out all the commercial issues, what is the best technology that can be offered to the industry?

“BPSA published a series of guides. To develop the first one (quality test reference matrixes) suppliers met to reach a consensus on best quality practices for their common equipment. such as bag, tubing, sterile connectors, and filter supplies. The resulting document was published in 2007, and is now being updated to add some technologies that were on the horizon back then, such as sensors.

“The next guide focused on gamma irradiation and sterilization. When we were working on this in 2007 many people in the industry were unfamiliar with gamma irradiation and how it was validated for sterilization. It's quite different from steaming. So the guide was a way to educate people to understand what was necessary and educate the FDA. People who have experience in sterile medical devices are quite familiar with it, but we find many FDA reviewers in pharmaceuticals did not know about the standards and practices for gamma sterilization. So the guide was helpful.

“BPSA then began to address harmonizing the approaches to extractables and leachables testing with a risk-based assessment. We published a guide in 2008 and we presented a one-day symposium to the FDA that was broadcast to CDER [Center for Drug Evaluation and Research] and CBER [Center for Biologics Evaluation and Reserach] in several locations. We've had some great dialogue with them. Since the publication of that risk assessment, the BPSA risk assessment has been adopted by many biotech companies. It has been submitted to the FDA, and the agency recognizes that risk assessment as a good approach. This is very useful because although you see FDA guidances that say you should take a risk-based approach, there's no guidance that defines a good risk-based approach. And how do you decide what's a real risk and what's not a real risk?

“BPSA also published a guide on the disposal of single-use components, specifically an economic analysis. In 2010, we did a second phase of our extractables guides, which discussed the analytical methods that should be applied to single-use. Initially that is intended to speak to suppliers so that they can start to apply common conditions and common analysis. It also serves to educate users and regulators on what the best practices are.

“Another current project that BPSA is working on now is a consensus quality agreement template. Many end-users and suppliers tell us that they spend months, sometimes years trying to negotiate appropriate quality agreements. Everyone recognizes how important these are for single-use, but there's not a lot of agreement about what needs to be in it. It's quite difficult for a supplier to deal with multiple quality agreements from different customers. It's also difficult for a customer to deal with different quality agreements from suppliers. So everyone agreed that if we could come up with a consensus that covers 75–80% of what needs to be in a quality agreement, then just the remaining part would have to be negotiated. We expect to have that out next year.

BPSA has an extractables task team working on related issues such as standardizing initiatives, working with BPOG and ISPE. We also have a particulates task force, which is a joint effort between suppliers and users to help find best practices for the suppliers to reduce the risk of particles in single-use systems.

“As part of our forum mechanisms we have what we call a supplier roadshow, where BPSA suppliers come together into your end-user facility and provide a day of training and hands-on with all of the equipment. Other than the table tops it's not commercial. And we've done this at a couple of venues or facilities now. And they've said it's extremely valuable because we can reach several hundred of your employees in one day locally, without their having to travel. And it's cost effective to the suppliers to reach out to potential customers. And it's cost effective for end users.

“Finally, BPSA holds an annual single-use summit meeting where we have key people and topics. And a lot of these topics that I've just gone through are what have been discussed there. Coming up in the next year we'll be meeting with the BPOG group on evaluating extractables and leachables qualification proposal. And as was mentioned earlier, we have people that participate with PDA on the single-use technical report that are on the task group for BPE extractables and leachables and USP and forums like this.

“We're not a standards organization. Our guides are intended to be stimuli to other organizations. And we've been successful and effective with that based on what you see going on now. This is part of the growth of single-use. What we're getting are the thoughts and inputs of all of the knowledgeable people in the industry — regulators, end-users, and suppliers so that we will ultimately build what are the best practices and standards for single-use.

User Group Additional Resource

The BioProcess Institute has facilitated a newsletter focused specifically on the progress being made in the harmonization and standardization of single-use technology. “After that [2013 BPI Conference] meeting in Boston, we decided to continue having monthly teleconference meetings and periodic public ‘Town Hall’ meetings and to publish what was discussed in this newsletter,” says Vogel. The first issue was released in January 2014, and future issues are planned.

Author Details
Maribel Rios is managing editor of BioProcess International; 1-646-957-8804. Information about the Single-Use Newsletter should be addressed to James D. Vogel at the BioProcess Institute, 401- 294-9000; jvogel@bioprocessinstitute.com; www.bioprocessinstitute.com.

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