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. 	

 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.	

 "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.	

 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."	

 "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."	

 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."	

 "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. 	

 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. 	

 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. 	

 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."				

 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.	

 "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."	

Articles

Columns and Departments

Biopharmaceutical manufacturers face many bioprocessing concerns including safety, flexibility, maintenance, capacity, capital investment, and process costs. Disposable products can reduce some of the burden.

BioTrends: Disposable Processing Systems: How Suppliers Are Meeting Today's Biotech Challenges from Fluid Handling to Filtration

Outsourcing validation studies can help a company meet deadlines by supplementing existing staff and supporting specific projects. Securing the maximum benefit from a validation contractor, however, requires a systematic approach and clear communications. A long-term outsourcing relationship begins with a proposal, which describes your requirements accurately and in sufficient detail. 	

A proposal enables the client and contractor to work in parallel to accomplish their common goals. Scheduling exercises (such as practice interviews), delineating project specifics, and building a long-term relationship minimize the gap between client expectations and what a contractor can achieve.	

The precursor to many outsourcing mishaps lies with an inadequate proposal. The proposal sets a project's tone and scope by emphasizing the goals, timelines or assignment durations, and critical assumptions. 				

 A proposal should include a detailed section on critical assumptions - to make the document more accurate and to ensure both parties begin operating with the same premises - once the contractor is selected. The section on project-related assumptions can include the following items:	

The proposed budget does not cover equipment rental costs.

Temperature mapping includes one run per unit.

Time is not allocated for resolving deviations, which are the client's responsibility.

The client will provide a workstation that includes a personal computer, email access, a phone and fax, and work supplies.

Time is allocated for only one review of protocols and reports.

 Project managers need to detail the intricacies of their projects rather than presume a contractor can deduce the information from the proposal. A proposal that is limited, either in its lack of detail or formality, will yield a project that requires more of the project manager's time and more direction given to the contractor. It is incumbent upon both the project manager and the contractor to ensure the proposal is a formal accounting of all expected details.	

 Project managers need "people" skills; they need to be able to communicate clearly and succinctly. Soft skills, in an outsourcing relationship, have their genesis in the proposal. They foster a sense of trust and common respect, a shared level of commitment, project knowledge, and direction. 	

We recommend a contracting strategy that focuses on a phased plan for hiring contractors, emphasizing both the "hard" and "soft" components. The four phases are up-front work, an on-site foundation, project implementation, and project maintenance.				

 Remember this phrase: "Do your homework." 

in this context can be defined as knowing your contract and your contractors.	

Once the decision has been made to hire a contractor, ensure the contractor's capabilities meet your needs - that is, do your homework. To be compliant and to incorporate industry's best practices, engage in these up-front activities:	

 Hold an informal meeting to gain insight into the contracting company's goals and mission - and most important, its staff experience. Use this time to ask both detailed and general questions, such as:	

What are some of your current and past projects?

Does your skill set overlap our needs on this project?

 Once you have narrowed the contractor list, ask to review staff resumes.	

 Meet the potential candidates. Invite the contractors to visit your facility, and conduct a short interview. This can be accomplished in an informal or formal setting. Conduct a plant tour while interviewing, or have the contractors meet some of your current staff to help you gain a deeper insight into the contractors' relevant work experiences. If time does not permit such in-depth contact, a telephone interview can suffice.	

 Request a proposal. During proposal generation, it is imperative to develop accurate plans so that clients share pertinent project details. That information can include equipment lists, timelines, financial restrictions, equipment rentals, and project expectations. Sharing this knowledge empowers the contractor, and as a result, you receive an authentic, customized proposal.	

 Review and approve the proposal. The proposal sets the tone for the life cycle of the project. Both parties must agree on the details of the plan.	

 Allocate sufficient time for security measures. The contractor may be subject to specific security measures, such as a background check. Be sure this time is reflected in the project start date.	

 The on-site foundation phase of an outsourcing contract offers an opportunity for active conversations that cultivate a commitment to the project, foster trust, and establish communication channels. This phase should include ample time for the contractor to become familiar with your company culture, its style, and the project teammates. On-site initiation can take a half-day, a full day, or a week, depending on your project requirements. On-site time involves the following steps.	

 Be prepared for the contractor's arrival. Take appropriate measures to ensure the space provided to the contractor is conducive to project work. Ensure that computers are set up and have network connections and email, that access cards are available, and necessary supplies are on hand on the first day.	

 Cultivate trust and commitment to the project by establishing a good, two-way communication channel between the project manager and the contractor.	

 Conduct a tour of the work area and the plant. At the start of the project, be sensitive to contractor needs in their new work environment. In larger facilities, a single plant tour may be insufficient.	

 Introduce the contractor to both the validation staff and the others who are involved in the project.	

 Provide general training material to the contractor. Focus on providing training material on daily operations, such as the validation master plan, templates for protocols, and gowning procedures. We have all read standard operating procedures that left us confused or that are forgotten until we are actually using the procedure. It is important that clients focus on specific procedures that are used in later stages of the outsourcing project. 	

 Share your organizational charts. Project charts that show your company's hierarchy visually summarize staff roles; provide a guide for contractors when they need to determine appropriate communication channels; and inform contractors about key project players.	

 At this point, hours or days have been well spent crafting a solid, up-front foundation for the contractor. The objective of the project implementation phase is twofold: Delineate project needs, and provide further validation or project-specific training.	

 Reiterate the proposal. Confirm that the contractor understands your expectations. Review equipment lists, deadlines, and milestones.	

 Discuss the significance of the project: Is the validation a small-scale effort, or is it a corporate-wide goal? This determination influences other aspects of the project. 	

 Identify project dependencies; that is, inform the contractor of the people who directly affect the validation effort, typically through lateral relationships. Ensure that the contractor has met these people and knows how to contact them.	

 Allocate time and staff to provide training. A contractor can review the material received and be trained "in the trenches" on specific procedures.	

 To avoid delays, inform the contractor where equipment is stored and how to sign out equipment.	

 Take a backseat. Let contractors do their jobs; that's what you pay them for.	

 As a validation effort unfolds, there are victories and causalities, but the momentum of the project must continue at a quick pace. People need to stay motivated, positive, and excited about their work and validation. Project participants turn to their leader for support. Success tips for orchestrating project maintenance include	

Take a backseat, but be a backseat driver. Keep aware of the progress and direction of the project.

Stay involved and communicate. Engaging in face-to-face discussions with a contractor can provide you with deeper insight into the details of the validation project.

Continue to foster the necessary lateral relationships (project dependencies). As the project unfolds, so do the relationships. 

Energize staff by stating and restating the benefits of the contractor's effort. Focus on the benefit of the finished project.

Use mishaps and deviations as opportunities to reflect and learn. 

Give recognition when deserved. Encouragement - a simple "good job" - can motivate the whole team.

This four-phase outsourcing strategy has several steps that can occur simultaneously, driven by the time scheduled for the project. But information from each step is important to your company and to the outcome of the project. By capturing the information from each step, you ensure that you know your contract and contractor and that you are aware of the project progress at each stage.				

Experience teaches that successful validation efforts - those that maintain regulatory compliance - are achieved by orderly and timely commencement and continued project management. Staffing a validation department, however, can be difficult if qualified candidates are limited. Too few personnel or staff without the proper experience will affect the polished plan you want. As many companies have discovered, the capabilities of validation contractors can be used to supplement your current staff and facilitate successful validation projects. 

Good Outsourcing Practices

Supplementing your existing staff with experienced contractors when your process is ready for validation can help you avoid common validation mishaps - if you know the ingredients of successful project management.

Validation Outsourcing: Getting the Most Out of Your Client?Contractor Relationship

During the past few years, several people and organizations have stated public positions on the feasibility of creating a legal and regulatory framework for the facilitated approval or licensure of biologics, based on abbreviated applications (1-3). However, public debate on follow-on biologics is difficult because of the considerable complexity of the interrelated technical, legal, and regulatory issues. Inappropriate use of biologics terminology and misconceptions of the regulatory grounds for safe approval of biologics result from an incomplete understanding of the basis for approval of existing biologics within the same therapeutic category. We seek to clarify some of these issues in this article. We maintain, however, that the regulatory process for the approval of biologics must be shaped by three cardinal principles:	

The safety of patients is of primary concern. Biologics are associated with clinical issues not shared by chemical drugs. This necessitates appropriate clinical testing of all follow-on products.

The approval process for any biologic should recognize the ownership and value of the innovator's intellectual property, including data submitted for regulatory approval and licensure. 

All aspects of the regulatory framework should be supported by sound science of the same rigor as that used in the original approval of the innovator's product.

A biologic is a prophylactic, an in vivo diagnostic, or a therapeutic substance that can be made only by a living system and that has a large, complex, inherently heterogeneous molecular structure.

Biologics have been defined in disparate terms, depending on the scientific, regulatory, or legal context - no comprehensive and universally precise definition exists. For the purposes of discussion of follow-on biologics, we use the following operational definition:	

A biologic is a prophylactic, an in vivo diagnostic, or a therapeutic substance that:	

is produced only by a living system, but is not simply a metabolite,

is stated to contain a single substance that has documented biological activity or activities,

has a relatively large molecular weight with a high structural complexity compared with biologically active substances that can be made by chemical synthesis (in practice, this means that biologics will seldom have molecular weights less than 5 kDa),

is inherently heterogeneous in the molecular species present and has an impurity profile that depends critically upon the processes used to make and test each batch,

has activity that is often very sensitive to physical conditions (temperature, shear forces, phase) and enzymatic action,

usually requires bioassays for batch release and stability assessment, rather than chemical tests for identity and purity.

A "generic" drug is approved by reference to a strict definition of sameness to the innovator's product. Sameness, however, cannot be determined for biologics from different manufacturers because of the complex nature of the products and their manufacturing processes. Therefore, "generic biologics" produced by different manufacturers cannot exist.

The phrase "generic biologics" is often used to mean products that would be copies of, and be competitive with, biologics produced by pioneers (that is, innovative companies that developed and produced the first version of a particular product). FDA would approve these products by reference to the clinical data generated by the pioneer. This designation is derived from the regulatory process for approval of generic (chemical) drugs, which was created by the Hatch-Waxman amendments legislation of 1984 (4) and is codified in Â§505(j) of the Food, Drug, and Cosmetic Act (FD&C) (5). However, because of major technical differences between drugs and biologics, FDA stated that the regulatory process under Â§505(j) would not be appropriate for the approval of biologics because it would result in the approval of unsafe products (6). More recently, FDA Commissioner Mark McClellan stated that, "As a scientific matter, it is true that certain biological products, due to their inherent structural complexity, heterogeneity, and manufacturing process, do not currently lend themselves to being copied generically" (7). 	

Because the "sameness" standard under Â§505(j) defines the correct use of the word "generic," and the properties of biologics do not allow the standard of "sameness" to be met, there can actually be no "generic biologics." 	

"Follow-on biologics" are second and subsequent versions of biologics that are independently developed and approved after a pioneer has developed an original version. Follow-on biologics may, or may not, be intended to be molecular copies of the innovator's product. They do, however, depend on the same mechanism of action and are intended to be used for the same indication.

Currently, follow-on biologics are approved or licensed by submitting to FDA a full product license application - either a New Drug Application (NDA) or a Biologic License Application (BLA). Those products that have been approved or licensed are not copies of the original, innovative product. They resemble instead the innovative products in much the same way that members of a class of drugs resemble each other (statins, triptans, and H2 antagonists, for example). It is possible that some follow-on products could be approved safely on the basis of fewer or smaller efficacy studies than were required for the approval of the pioneer. Table 1 gives some examples of innovator and follow-on biologics.	

The concept of "follow-on biologics" or "generic biologics" does not include the special circumstances in which a manufacturer may make changes to its production process without conducting new clinical trials (see the answer to Question 10 for further explanation).	

4. Why would follow-on biologics matter to the innovator industry? 

With the success of the Human Genome Project and investments in genomics, bioinformatics, and proteomics by pharmaceutical companies and others, biotechnological medicines (therapeutics and preventives) present new opportunities for innovation and powerful, new therapeutic modalities. These therapies have already provided important new treatment options and, in some cases, revolutionized the standard of care for certain diseases. The promise of these modalities is even brighter. Patient confidence in the safety and efficacy of these products, however, must be maintained. 

Another more subtle concern exists for regulators and the pharmaceutical industry. Chemical drugs have simple chemical structures, which can be completely characterized and specified. The Hatch-Waxman Act, therefore, established very rigorous standards of identity (sameness) of generic drugs to innovator drugs for the approval of those generics under Â§505(j) of the FD&C. Biologics and biotech drugs cannot be approved under Â§505(j) the same way, except by attenuation or violation of that sameness standard. Unlike chemical drugs, individual batches of biologics are heterogeneous at the molecular level as a result of the inherent random variability in the living processes by which they are made. These molecular differences are even greater between versions of the same molecule produced by different manufacturers. Therefore, approval of biologics under Â§505(j) would not only mean approval of products with uncertain clinical properties but would also set a precedent under which drugs significantly different from the innovator drug could be approved as generics. That would destroy the careful legal balance between the innovator and generic industries that was framed in the Hatch-Waxman Act and would have adverse consequences for the control of drug costs and public health.

Table 1. Some examples of innovator and follow-on biologics	

5. Does the recent move of therapeutic product review from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER) indicate a change in the standards for approval of follow-on biologics? 

There is no evidence to support this speculation. 

Both CBER and CDER have been intimately involved in the creation of harmonized standards for biotechnological and biological products as part of the International Conference on Harmonisation (ICH) and under the FDA Modernization Act of 1997 (FDAMA) during the past decade. In announcing the recent move of CBER's Office of Therapeutics Research and Review (OTRR) to CDER, Lester Crawford, FDA deputy commissioner stated, "Current FDA policy on generic biologics will not be affected by this decision" (8). As quoted earlier, FDA Commissioner Mark McClellan has agreed that biologics do not lend themselves to being copied generically (7). This position has been common to both CBER and CDER for many years and is manifest in the fact that neither Center has approved any follow-on protein therapeutics under either the Public Health Service Act (PHS) or the FD&C Act. So despite the recent reorganization within FDA and the possibility of more in the future, there is presently no evidence that the standards by which biologics are approved are going to change.	

6. Safe (chemical) generic drugs have been on the market for years, proving that abbreviated data packages (that is, with no safety and efficacy testing) can ensure the safety of generics: Why not apply this approach to biologics as well?

Safe generic drugs have been approved with abbreviated data packages because it is possible to show that the generic product is chemically and pharmaceutically identical to the pioneer's product, to within very tight confidence limits. Therefore, it is scientifically reasonable to expect that the clinical properties of the pioneer's product will be shared by the generic. Because the follow-on biologic cannot be shown to be identical to the innovator product, this relationship does not hold for biologics. 

The manufacturing process for each biologic defines, to a significant extent, the product because biologics are based on living cells or organisms whose metabolisms are inherently variable. Moreover, apparently small differences between manufacturing processes can cause significant differences in the clinical properties of the resulting products. For example, when the manufacture of tissue plasminogen activator (tPA) was changed from production in roller bottles to production in stirred bioreactors (tanks), the resulting product showed differences in its glycosylation pattern and degree of internal cleavage and possessed a different pharmacokinetic profile and dose response in humans. 	

There will always be differences between manufacturing processes designed by different manufacturers, especially those in competition with each other. As we stated, it is not possible to predict what the effects of these differences might be on the clinical properties of the two products. Therefore, it is not scientifically reasonable or safe to simply expect that the clinical properties of a pioneer's product would be shared by the follow-on product. The only way to characterize the clinical properties of the follow-on product is to evaluate them in appropriately designed clinical studies.	

7. There are several versions of recombinant insulin, human growth hormone, and alpha-interferon on the market - so don't we already have generic biologics?

These products are not generic, because the approval or licensure of each product was based on evaluation of full sets of independent data. 

Different manufacturers - as independent innovators - have developed each of these products and compiled complete regulatory applications, based on unique product, process, and clinical data sets. These applications received full and independent review by FDA. They cannot be presumed to be substitutable for each other (that is, they are not AB-rated, for bioequivalence, in FDA's Orange Book) (9), but they can represent therapeutic alternatives. A label claiming substitutability can only be supported by an appropriate clinical trial comparing the safety and efficacy of the product directly.	

8. Because there can be only one innovator for each biologic, aren't follow-on products generic biologics?

It is not accurate to say that there can be only one innovator for each biologic.

There are many instances of multiple manufacturers of therapeutically alternative biologic products on the market (growth hormone, insulin, Factor VIII, erythropoietin, and tPA, for example). Each of these alternative biologics were independently studied and demonstrated to be clinically safe and effective. Independent clinical trials were conducted for each. Interestingly, even though these products might appear to be similar, there can be differences between their clinical properties. For example, Betaseron (Berlex Laboratories) and Avonex (Biogen, Inc.) are both versions of beta-interferon used to treat multiple sclerosis. Avonex has 166 amino acids, whereas Betaseron has 165; Avonex is produced in mammalian cells, whereas Betaseron is produced in bacteria. Incidents ofpatient adverse events differ between the two products. These differences between the products are of the same order as differences between members of a drug class (see the answer to Question 3).	

Likewise, the amino acid sequences of the alfa-interferons Intron A (Schering Corporation) and Roferon (F. Hoffmann-La Roche Ltd.) also differ by one amino acid. The licensure by CBER of these two products on the same day - on the basis of independent clinical trials - shows clearly that there can be multiple innovators for each biologic.	

9. In Europe, a product made by recombinant technology (Forcalcitonin) was shown to be bioequivalent to the pioneer's product and was approved on the basis of an abridged application. Isn't this a true generic biologic?

Forcalcitonin (Unigene Laboratories, Inc.) is not a true generic biologic.

Forcalcitonin is produced by expression of the gene for calcitonin from salmon, but the product is an oligopeptide containing only 32 amino acids, which does not satisfy our definition for a biologic (see the answer to Question 1). Forcalcitonin can be produced by means other than a living system; indeed, the pioneer's product, Miacalcic (Novartis), is produced by chemical synthesis. Forcalcitonin and Miacalcic are drugs (pharmaceuticals). The fact that Forcalcitonin was produced by recombinant technology is not relevant to the discussion of generic biologics.	

10. An innovator is able to make changes to its manufacturing process without doing further clinical trials. Why can't a generic manufacturer set up a new plant and make the same product safely?

It is not true that an innovator can always introduce process changes without doing clinical trials. Whether that can be done depends on the nature of the change and the results of comparative product characterization studies. FDA still requires clinical validation of process changes in some cases.

The innovator has a comprehensive database of every step of the manufacturing process and key intermediates and has established many in-process controls and reference standards. Generally, changes are minor alterations to a well-understood, extensively validated and licensed process, with all other aspects of production remaining unchanged. The innovator is able to compare product made before and after the process change and show that the change has had essentially no effect on the product made. By contrast, a follow-on manufacturer does not have access to the pioneer's data, key intermediates, reference standards and reagents, and the complex or unique validated methods (such as bioassays) that would enable a comparison of the follow-on process with that of the innovator's. Even if all the pioneer's manufacturing data were available, the inherent differences in production and analytical methodologies, facilities, and reagents between manufacturers would render the data nontransferable (see the answer to Question 6). 	

Product Development Issues

In this question-and-answer discussion of "generic" biologics, the authors contend small changes in manufacturing of biologics dramatically affect the safety and efficacy of the therapeutic molecule.

Biologics: Can There Be Abbreviated Applications, Generics, or Follow-On Products?

Perhaps it is time to change the common paradigm that uses "war room" nomenclature to describe the document preparation activities during compliance inspections from regulatory agencies. "War" implies conflict - and ultimate winners and losers. In truth, the real loser in this situation can only be the sponsor. Rather than winners and losers, consider that inspections provide the opportunity for the sponsor to demonstrate a high level of competence and proficiency to regulators - regulators who are primary customers who exercise control over when and how a product will be marketed. 	

Previous articles (1–3) have described the preparation for inspections and the activities during inspections. This article describes the scope and depth of the responsibilities of coordinators, liaisons escorting inspectors,  and those who prepare documentation, and assemble staff or technical subject experts to meet with inspectors.	

Accurate, timely document retrieval, data presentation, and staff preparation are essential to a successful inspection outcome. The activities associated with the document preparation area and the coaching of presenters should be coordinated by a single individual. This person - the coordinator - ensures the right people are in the right location at the right time. The coordinator also fills in and performs whatever activity is rate-limiting at a given time. 				

Roles and responsibilities for each individual need to be developed and communicated before the actual inspection. All participants: liaison escorts, document preparers, subject matter experts, coaches, and "runners," should meet so the coordinator can explain how areas will function and interact. This meeting is important so that everyone can see how his or her activities fit into the overall process. If the inspection begins in the early afternoon, it is a good idea to briefly review responsibilities on the morning of the inspection and address any last-minute questions or concerns. Document and personnel flow can be diagrammed on flip-chart paper and prominently displayed on the walls of the document preparation area. This serves as a constant reminder of the process and will be referred to more than once when activities peak. 	

Company representatives - liaisons - who accompany the regulatory inspectors are responsible for:				

establishing and maintaining a positive relationship with the inspector

ensuring that data and requested information are accurate and address the issue

ensuring that presenters (subject experts) and documents are provided to inspectors in a smooth, consistent flow

anticipating requests and additional areas of inspector interest.

 An ideal ratio is to have one liaison for each agency inspector. Liaisons should have sufficient technical knowledge to work with the inspector to refine and document information requests, but they are not expected to respond to detailed technical questions. For example, when a request for "all validation protocols and data for the purification area" arrives in the document preparation room, it is not clear whether the inspector is interested in equipment installation qualification (IQ) and operational qualification (OQ), process validation, cleaning validation, or any of a variety of other possibilities. Returning the request for further clarification takes time and is disruptive to both the liaison and the inspector. Liaisons orchestrate the flow of documents and personnel to inspectors. When liaisons provide a smooth flow of data, documents, and staff to and from the inspectors, they eliminate the down time that frustrates inspectors. 	

 Some companies use three different individuals performing liaison tasks: one to accompany the inspectors, another to write requests, and a third to record discussions among different individuals. Companies may use "runners" to carry requests and documents between the liaison and the document preparation room. In selecting the approach to use, keep in mind the logistical difficulties that a large group can cause in a manufacturing suite or a conference room. Limit immediate participation to those who are essential to achieving the goal of a successful inspection.	

Document room staff perform a variety of activities, including:				

recording, prioritizing, and tracking of document requests

ensuring that complete records and copies are kept of all documentation provided to the inspectors. 

When operations in the document room function effectively, few people notice. But when there are difficulties in the document room, everyone notices, and the first to notice are the inspectors. 	

Behind-the-scenes activities are labor intensive and require a skilled group of individuals who work well together. The document room during an inspection is not the time or place for prima donnas or for staff who feel they have turf to claim or protect. Document area staffing should not be an afterthought. Staff working in the document area should be experienced and organized. 	

 Document preparation activities are labor intensive. For example, five recent preapproval inspections averaged five days each, excluding introductory meetings, facility tours, and the time inspectors spent writing and delivering the 483 observations. An average of 240 requests were made at each company, with a range of 154 to 364 requests (one inspection was likely an anomaly in the number of requests). Each inspector made approximately 12 requests per day with the peak number of requests during the last half of the inspection. Each request is not, however, addressed by providing a single document. For example, in an inspection during which 285 requests were made, 100 one-inch binders, almost 60 three-inch binders, and other material such as SOPs and batch records were retrieved, reviewed, presented, and stored. 	

Inspectors frequently request copies of documents or sections of documents. The volume of documents copied for regulatory inspectors to take with them can fill more than one cardboard box that holds standard-size file folders. The document preparation staff should retain copies of all materials provided to inspectors.	

 The document preparation room should be off limits except to necessary staff and should not be considered a social gathering area. Limiting access to this area minimizes the chance that important original documents get misplaced. Management, however, often likes to visit this room. Document room activities can seem chaotic, so it is useful to help management understand that this is actually a well-orchestrated activity. Before the inspection, brief management on the data collection, review, and storage activities that support the inspection. 	

An effective way to minimize disruption by management visits during the inspection is to post abbreviated versions of inspector requests on flip charts and hang the charts on the walls around the room. This way, management can ensure they understand the information being requested without disturbing the flow of activities. Management visits are also minimized or shortened by providing frequent lists of all inspector requests. 	

Requests for document or information should be recorded on a standard form that has been prepared for use during inspections. Request forms can be already numbered, or numbers can be assigned at the time the form is given to the document control group. Numbered requests serve as unique identifiers for tracking purposes, but do not establish request priority. When multiple documents are required to fulfill a single request, the identifier number should be placed on each of the documents. Frequently, the conference room table where inspectors work has dozens of documents spread out in various stages of review. Knowing which request each document supports is invaluable in keeping order in what might otherwise be a disjointed jumble of paper.				

Multiple documents from a single request.

 As stated, a single request can require collection of multiple documents. Moreover, follow-up requests may be made. It is important to decide - before the inspection - how such situations will be handled. Are initial and follow-up requests given different identifiers? Listing the initial inspector request on a single form, then using another form for each follow-up request can be efficient. 	

Effectively documenting and tracking requests during an inspection permit staff to identify the status of all inquiries at any time. This is important because multiple inspectors frequently make almost identical requests, or the same inspector wishes to review a document evaluated earlier in the inspection. Documentation can be effectively managed using a paper-based system if only one or two inspectors are present. Inspections with more than two inspectors can overwhelm a paper-based system and slow the document retrieval process. A company can use one of several adequate commercially available computerized programs (such as FileMaker Pro or Access). At a minimum, the database should record the specific request, the time and date that it was recorded, which inspector made the inquiry, the company liaison associated with that inspector, and the staff member providing the documentation. It is also valuable to identify and link follow-up inquiries with the original request. 	

Computerized databases allow staff to rapidly determine the number and status of outstanding requests at any time. Reports, sorted by requesting inspector, can be provided to the respective company liaison several times during the day. This assists liaisons in supplying a smooth flow of documents for the inspector's review. Reports can also be provided to management so that they are aware of the current status of the requests. 	

Documents provided should address the inspector's question and not provoke tangential queries that might negatively affect the outcome of the inspection. Tedious as it is, every page of all the documents provided to FDA should be reviewed to ensure that miscellaneous email messages - and those ubiquitous little yellow sticky notes - don't make their way to the inspectors. At times, a dozen staff members may be devoted exclusively to document review. This is not to suggest that the staff reviewing the documents should remove or correct unflattering or problematic information if that material is key to the request from the inspector. The review, however, serves to identify problematic items so that the presenter is prepared for the discussion and is not taken by surprise when the inspector "discovers" them. 				

The company should establish a means of rapid communication between the document preparation room and the presenters. Several phones should be installed in the document preparation room, and it is useful to reserve one of the phones for outgoing calls only. Subject matter experts can be provided pagers or cell phones to be used specifically for this activity. If pagers or cell phones are leased, it is prudent to perform a 100% check to make sure they all function properly rather than discovering a glitch during the inspection. Phone codes can be established. For example, a page reading "999" could indicate that the recipient should go immediately to the document preparation room. 	

Companies should identify the individuals who will be subject matter experts, able to address technical topics. Be sure to do this early in your planning process, so that you allow the experts sufficient time to prepare for this exercise. Interestingly, the appropriate individual for addressing a specific topic is 

 always the scientist with the most expertise on the subject. Subject matter experts represent the company to FDA, so they need to be knowledgeable, but they also need to be able to communicate clearly and succinctly. Subject matter experts should not view their task as a "heroic" position in which they will "save" the company. 				

Subject matter experts should understand what their role is during the inspection and should practice responding to difficult questions that inspectors may ask. Every company has vulnerable points in product development and validation schemes. Company experts who are able to deliver a confident, consistent response can mitigate the effect of a technical deficiency. It's far better to be prepared for the hard questions than to just hope that the regulatory agency doesn't uncover a weakness.	

Experienced quality assurance or quality control staff members are often effective in coaching subject matter experts immediately before their meetings with inspectors. An experienced coach can calm a nervous presenter and impart a last-minute dose of confidence.				

Coaches should ensure that subject matter experts who will address specific topics to inspectors are familiar with the data, the conclusions, the associated deviations or investigations, and any potential weaknesses in the documents they will be providing and discussing. Subject matter experts and the document review staff are jointly responsible for identifying any weaknesses to avoid being taken by surprise when an inspector raises an issue. Effective coaching ensures that subject matter experts presenting information understand the relationship between the documents requested and the commitments made in product registration applications. Equally important, the subject matter expert should understand the context in which this documentation request was made.	

Participating in inspections is challenging and stressful under the best circumstances, but it can also be a rewarding experience. The company should acknowledge the important contributions made by those participating behind the scenes during the inspection. That can mean, for instance, providing food and refreshments during the day. Rotating the lunch supplier ensures that staff is not eating the same turkey sandwich every day. Providing a variety of basic meals, coffee, tea, soft drinks, and cookies is a simple gesture that means a lot to the recipients.				

Successful inspections are the sum of successfully executed components, many of which go on behind the scenes. Activities that have a critical effect on the outcome of an inspection are seldom highly visible. The responsibilities of the company liaisons and the document preparation staff and the interaction between the two are key features of a successful inspection outcome. Neither document preparation nor liaison activities are stress-free. Planning and coordination, however, can substantially minimize the stress and also increase the effectiveness of the staff involved in an inspection. Timely tracking and staging of documents result in efficient use of inspectors' time (and may even decrease the duration of the inspection), an efficiency that should certainly affect inspectors positively. Procedures for document control minimize the possibility that irreplaceable original documents are lost or misplaced, a serious consideration for contract manufacturers that have many regulatory inspections and client audits each year. 	

	(1)	Unger, B.W., "Using a Model and Tools to Standardize the Preparation for a Preapproval Inspection," 

	(2)	Lavian, M. and Allen, P.W., "Survival Guide to FDA Inspections, Part 1: To Prepare or Not to Prepare, There Is NO Question," 

	(3)	Lavian, M. and Allen, P.W., "Survival Guide to FDA Inspections, Part 2: Conducting the Audit - Ready or Not, Here They Come," 

A successful outcome to an FDA inspection is the fruit of planning, preparing, and training. Cultivate confident employees who are appropriately coached and clear about their responsibilities.

Pieces of the Inspection Puzzle: The Magnitude and Scope of Behind-the-Scenes Activities During an Inspection

Serendipity has little to do with a successful manufacturing outsourcing relationship, but strategic planning does. So does picking the right partner, a key factor in any serious alliance. An understanding of the client's clearly defined needs, objectives, and product vision is vital, as is both partners' ability to grasp the other's expectations. A realistic attitude, flexibility, and trust are equally important attributes on both sides of the table. And the real glue that holds the partnership - and project- together, even more so than a formal contract or quality agreement, is the ability to communicate regularly and honestly with each other. As impossible as all that may seem, partnerships like these do exist in the biopharmaceutical industry. Here are lessons learned from the partners of two successful matches.	

Whether you contract for activities outside your core competencies or for shared or extended competencies, there are considerable benefits to be had if the outsourcing relationship is executed properly. In the case of contract manufacturing services, client companies consistently name the same three major benefits: speed to market, risk and debt reduction, and access to expertise, equipment, and experience. 	

Mark O'Mahony, head of process development, quality control, and manufacturing for the biopharmaceutical company TolerRx, Inc. (Cambridge, MA), says, "Outsourcing compresses our development timeline, primarily through access to the facility, equipment, personnel, and expertise that we may not have in-house. We avoid capital risk and debt and gain flexibility. In early stage development, you want to mitigate your risk as much as possible. Working with a contractor allows you to do that, and it also allows you to change direction fast." 	

TolerRx, whose development pipeline contains four monoclonal antibody products to induce, maintain, or remove immunological tolerance, outsources purification and aseptic filling functions to Laureate Pharma LP, a privately held contract manufacturing services firm headquartered in Princeton, NJ. Laureate's Michiel Ultee, senior director of biopharmaceutical development and operations, confirmed that the capital outlay for a clinical-phase production center falls anywhere between $50 million and $300 million. "To invest that kind of money in something with uncertain returns is risk-laden," he says. 	

Time is also invested constructing a facility, from site placement, beginning with local zoning concerns, to actual construction and validation of all the processing equipment, including bioreactors and chromatography stations. Validation of a large piece of equipment can take three to five months, according to Ultee, so it could be up to a year to fully validate all the equipment. "It's a totally different timeline than, say, constructing a bank," he adds. 	

TolerRx continually assesses its make–buy decisions, and a balance of both has been the best way forward to expedite the way to the clinic, shares O'Mahony. The company seeks current  good manufacturing practices (CGMP) and current good laboratory practices (CGLP) outsourcing support for its preclinical and clinical trials with several manufacturing and testing facilities at any one time, depending on the available capacity, scale, and technical capabilities. TolerRx's core competency in biologics manufacturing, as well as cumulative successful experiences working with different antibodies in an outsourcing capacity, give it the confidence to consider outsourcing as a viable alternative. 	

If using contract manufacturing services is a strategy you're considering for the future, or if you've experienced unfortunate circumstances in a prior outsourcing relationship, first identify your process requirements and establish your project timeline before starting your candidate search. Alexion Pharmaceuticals, Inc. (Cheshire, CT), which develops novel antibody therapeutics for human diseases where treatments are either inadequate or nonexistent, has used various manufacturing outsourcers since 1996. Eric Frieden, its director of fermentation and cell culture development, believes these two elements are key criteria and will help considerably to narrow the candidate pool. Analyzing your needs ahead of time helps you recognize more of the synergies with respect to scale, expertise, techniques, capacity, and availability.				

"Analyzing the outsourcers' capabilities, as well as evaluating the cost factors, are other key criteria," explains Frieden. "Determining their long-term interest is also an important consideration. Once you start working with someone, there's a huge cost - in both dollars and time - in changing partners." 	

Not only is expertise a consideration, but particular experience in the functionality you seek and the outsourcer's regulatory experience should factor into the equation, too. One of Alexion's manufacturing and development outsourcing partners, Lonza Biologics (Portsmouth, NH), is a case in point. Glyn Forster, its head of product management, explains that the company has over 20 years of experience in successful interfacing with numerous regulatory agencies. For example, it has had nine successful inspections in the past two years - six in the United States and three in the United Kingdom. Alexion outsources various functionalities to Lonza, including development and manufacturing of its drug Eculizumab.	

Exercising due diligence during the outsourcing selection process is a natural and prudent component of the discovery phase. Some fact-finding now will yield dividends later. Is the outsourcer dedicated strictly to outsourcing, or does it provide outsourcing as a secondary function after performing the same functionality for itself? How many active projects does it currently handle? Does it matter to you? To some it doesn't, to others it might. 				

Does a customer's size, either in the complexity or magnitude of its needs, make a difference in the service it receives? How many customers does it support? "That's a double-edged sword," says Frieden. "Too many is not good, but too few is not good either." 	

Potential client companies often conduct preliminary audits at the candidates' facilities, meeting with staff to discuss their expertise and experience. It's an opportunity to see if personalities  "click," and to speak with the scientists, technical personnel, and project manager who would be assigned to the project. A site visitation should include auditing the contractor's quality assurance and quality control systems for compliance. "In addition to technical capabilities, compliance of the contractor's quality systems is probably one of the most important parts of our selection process," says TolerRx's O'Mahony. And finally, as in all industries, references and reputation speak volumes - so check around.	

It needn't be said that close attention must be paid to all the data presented in a proposal or contract. But outsourcing partners agree there are certain details that can be the source of later confusion or discord, so it's crucial they are thoroughly covered in the documentation. 				

Working with a contractor reduces time-to-market, risk, and debt, while providing expertise, equipment, and flexibility - but those benefits accrue only if you plan and communicate with your outsourcing partner.

BioPharm International-07-01-2003

BioTrends: Disposable Processing Systems: How Suppliers Are Meeting Today's Biotech Challenges from Fluid Handling to Filtration

Validation Outsourcing: Getting the Most Out of Your Client?Contractor Relationship

Biologics: Can There Be Abbreviated Applications, Generics, or Follow-On Products?

Pieces of the Inspection Puzzle: The Magnitude and Scope of Behind-the-Scenes Activities During an Inspection

Inside the Outsourcing Relationship

Inside Washington: Debate Escalates Over Follow-On Biologics

Outsourcing Outlook: A Capacity for Excess