By Robert Roy and Jason Collins, IPS
Today's disposable systems offer improved manufacturing efficiency, and better QA and regulatory compliance — and they can be the fastest route to media fills
The introduction of cellulose-based disposable diapers in the early 1960s saved mothers countless hours of rinsing, washing, drying and folding cloth diapers.
Similarly, single-use disposable systems (SUDS) for aseptic fill/finish units promise to save pharmaceutical manufacturers valuable time, streamlining operations as well as shortening project schedules. Incorporating SUDS can also offer regulatory compliance and environmental, health and safety (EHS) benefits as well as facility design advantages.
Bulk biotech operations have successfully deployed single-use systems for buffer and media preparations for some time, and they are currently implementing new single-use technologies such as fermentation and chromatography systems. Recent advances in technology are making SUDS increasingly attractive for aseptic operations. A single-use line is a particularly good fit for parenteral solution products with relatively low batch sizes (50L to 500L) that can be transferred by peristaltic pump.
Operations in an aseptic fill/finish line range from the various activities involved in formulation to filtration and solution transfer to dose forming. Today's disposable systems enable manufacturers to take advantage of this approach throughout the operation. SUD components are available for mixing, addition of liquids or powders, filtration and transfer as well as dosing and sampling. Equipment can be sourced from an increasing number of vendors representing various technologies. Some examples are discussed below:
Bag mixing systems are available from a number of vendors, including Millipore, Sartorius Stedim Biotech (SSB), Hynetics, and ATMI. Available single-use technologies include magnetic and disk mixers, as well as levitating impeller technology, all of which use disposable mixing bags. Systems are available in sizes ranging from 10 to 5,000 liters. Disposable feed bags from HicoFlex, HyClone, ATMI and others allow the addition of powders, and single-use sterile connectors in a variety of configurations from Colder, Millipore, Pall, SSB and others enable sterile fluid transfer.
Multiple vendors offer single-use bags made of films with low extractables. Most can offer baseline validation packages that, while not product specific, can be used as a starting point for evaluation. Sartorius, for example offers a validation package confirming that its films are designed, manufactured and sterilized under conditions that mirror biopharmaceutical operations and meet current Good Manufacturing Practices (cGMP) requirements. Bags undergo in vitro and in vivo biological reactivity tests and tests for plastic and meet standards for particulate matter in injections, bacterial endotoxins, bioburden and sterilization of medical devices.
Bag configurations are customizable, with a wide selection of fittings and tubing. Bags arrive at the facility pre-assembled and sterilized; each batch comes with a certificate of conformance from the manufacturer and a record of sterilization, simplifying documentation requirements.
Similarly, a number of vendors offer single-use filtration components in a range of sizes and porosities. For years, these filtration components have been widely used in aseptic fill finish.
When evaluating single-use systems, keep in mind that supply chain security is a consideration. Once a specific bag film has been validated for use with a product, continued availability of that film is of paramount importance. The same is true of other components, such as connectors. Manufacturers may wish to pursue parallel qualification of at least two different films for supply chain security. Parallel qualification minimizes associated costs and provides project timeline security in the event that an issue arises with one of the films.
A variety of technologies can be considered for single-use dosing systems. Recent improvements in speed and accuracy have made peristaltic filling systems — widely used in clinical filling programs — an attractive alternative to reusable positive-displacement pumps or time/pressure filling systems for commercial-scale dosing of virtually any product. Systems are available from such vendors as Bosch, Groninger, Inova and IMA.
From a technical perspective, peristaltic filling provides a simple, inexpensive fluid path and low-shear filling. Servo-drive pumps and advanced pump head geometry improve speed, and today's peristaltic filling systems are comparable in accuracy to positive displacement systems. At the end of the batch, the tubing is simply removed from the pump head and discarded, eliminating the need to clean the pumps. This offers an ergonomic advantage when the system is used inside an isolator. Tubing on some systems is even designed to be changed out with one hand.
Manufacturers who are already committed to a filling technology can still consider single-use options. For those who use rolling diaphragm filling technology, Bosch offers a disposable pre-validated, pre-assembled, pre-sterilized (PREVAS) diaphragm pump, which can be retrofitted to replace stainless steel components on existing lines or purchased for new equipment. Groninger offers a disposable single-use rotary pump. Another option to consider is a system capable of multiple dosing capabilities on the same piece of equipment.
Sampling has long involved a single-use approach. Today's single-use sampling systems are more sophisticated than a disposable sample cup. Sampling systems from Gore, Allpure, Novaseptum and others allow for aseptic single-use sampling for in-process quality control (QC). Although aseptic single-use sampling is relatively new, it has been used successfully in bulk biotech operations for drawing samples from fermenters and similar applications.
Positive Impacts on Process
Throughout the filling and finishing process, SUDS offer several benefits compared to reusable systems. Manufacturers using SUD technology can realize significant increases in process efficiency, with a major reduction in decontamination process requirements and washing/autoclave cycles, as well as elimination of the need for cleaning in place/sterilizing in place (CIP/SIP). As a result, both set-up time and overall turnaround time are reduced. Schedule reliability improves with fewer variables related to cleaning and sterilization.
For example, one manufacturer considering single-use technology produces approximately 1,200 batches per year on four to five conventional lines, which utilize CIP/SIP positive-displacement pumps. After each fill is completed, CIP/SIP of the pump station is required, a process that takes five to six hours. The company is testing a single-use peristaltic filling system that would cut turnaround time to approximately one hour, considerably increasing production capacity. Instead of cleaning, it will pull out and discard the used tubing and replace it with pre-assembled, pre-sterilized fresh tubing sets. The switch to SUDS will also result in a huge reduction in the volume of purified water that the company now requires for cleaning.
Along with enhancing process efficiency, the move to SUDS can also lead to documentation improvements, because fewer batch record documents are necessary.
With a single-use system, there is an incoming quality assurance/quality control (QA/QC) check when the disposable materials arrive to verify documentation such as Certificate of Conformance from the vendor and sterilization documentation. Another entry is made when a bag or connector is used—but there is no need to generate "after use" records documenting cleaning or sterilization cycles for traceability, or for the time-consuming process of reviewing, approving and correcting the documentation.
The Project Perspective
When establishing a new facility or a new production line, the integration of SUDS can streamline the project schedule by reducing or eliminating the need for installation and operational qualification (IOQ) of cleaning equipment and cleaning validation, or performance qualification (PQ) testing requirements. In many cases, SUDS also reduces up-front sterilization validation requirements, for example, by eliminating fill pump/tubing autoclave PQ testing. One of the strongest points in favor of SUDS from a project perspective is the fact that use of disposable technology may lead to faster achievement of a key milestone: media fills. Eliminating the up-front cleaning and sterilizations can easily cut six to eight weeks from the project schedule.
In addition to shortening the critical path for project completion, adoption of SUD technology can improve regulatory compliance and environmental, health and safety (EHS) profiles. Inadequate cleaning or sterilization of reusable components can have negative consequences ranging from batch rejection or product recall to plant shutdown—with enormous associated costs. Disposing of components after use reduces the risk of product cross-contamination, thereby improving the facility's cGMP compliance profile. Pre-assembled, pre-sterilized components also provide a sterile fluid path that improves sterility assurance.
Use of disposable components can help increase safety by reducing the potential for operator exposure to highly potent materials that can occur during disassembly and pre-washing of reusable components. With less need for cleaning and chemical neutralization, SUDS can also reduce a facility's hazardous waste stream and energy costs. SUDS need less water for injection (WFI) and associated equipment, as well as less clean steam. The reduction in energy use can contribute to sustainable design and Leadership in Energy and Environmental Design (LEED) credits. When disposal of single-use components is an issue, at least one vendor can reclaim and pelletize used bag film.
Use of SUDS can provide great flexibility for both new facilities and retrofits, as space requirements are generally lower and personnel and equipment flows are simpler.
A facility that reuses its equipment must be designed to support the proper flow of components from soiled equipment staging, washing, sterilization prep, sterilization and clean equipment staging. It requires large suites for washing, preparation and sterilization. In a reusable facility, soiled equipment must be staged prior to breakdown and cleaning, which requires space. Decontamination can be particularly challenging in a facility that handles biologics, as reusable parts must be decontaminated before cleaning. Operators must use appropriate personal protective equipment (PPE) in order to prevent exposure during disassembly and pre-washing.
Such a facility needs costly CIP/SIP stations, which usually are placed in a separate room to manage the safety risk associated with their steam lines. The facility also requires cleanroom storage space for staging dirty portable vessels, containers and reusable tubing and hoses as well as large staging areas for clean equipment. Use of disposable parts/systems eliminates or significantly minimizes these issues.
In general, single-use technologies make it possible to streamline equipment and personnel flows, especially in multi-product facilities. Depending on the extent of SUDS implementation, the capacity requirements of component prep areas can be significantly reduced. With less equipment to wash, the size and number of cabinet washers can be minimized. Without the need to sterilize stainless steel tanks, smaller floor-mounted units can replace pit-mounted autoclaves. Manufacturers working with high-potency compounds or live/attenuated viruses will not need to autoclave contaminated single-use components right after usage. SUD equipment can be placed into bags, which are externally decontaminated in vaporized hydrogen peroxide (VHP) chambers prior to internal decontamination elsewhere in central locations for incineration or autoclaving. This method reduces the total number of autoclaves as well as the space required for loading, unloading and maintaining them. Without re-usable portable vessels, there is no need for CIP/SIP stations or chemical storage areas for the corrosive solutions used by them. SUD systems do not need to be product dedicated, eliminating the need for dedicated tanks, hoses and other reusable product-contact parts as well as the space needed to stage them. A SUD system greatly simplifies the flow of materials. The single-use components enter the facility and are kept in a staging area until they are transferred directly to the process manufacturing suite, where they are assembled for production. After production, they may undergo dry fog or VHP decontamination before finally being disposed of through incineration or other means.
Space requirements can impact both construction and operational costs, and should be considered when weighing a reusable versus single-use approach. For example, in facilities that use reusable product tanks, tuggers are required to transporting heavy tanks from process suites to wash areas. Rooms and corridors must be large enough to accommodate the turning radius of the tugger/tank assemblies, and airlocks must have adequate space to allow interlocked doors to open and close. Door and corridor heights must be sized for the largest vessels. This requirement often drives the need for 10-foot-high doors and 11-foot ceilings to allow for 500- to 800-liter tanks with top-mounted agitators to pass. Most single-use bag mixers are not as tall as these reusable tanks, allowing the use of standard doors and ceiling heights. Reduction in room size and ceiling height reduces the volume of clean air that must be moved through the facility — and thereby reduces the associated energy costs. By allowing for lower ceiling heights, SUDS could cut air volume by 10% or more.
Already widespread on the bulk biotech side, SUDS is poised to become commonplace in aseptic manufacturing in the next several years, and customers will come to expect its availability. Organizations looking to design single-use facilities can already take advantage of multiple-vendor sourcing and can choose from proven technologies for various unit operations. The fact that SUDS are mature products makes a change from reusable to disposable a less risky decision. Many key questions—e.g., Can disposable tubing be sterilized by radiation? Will the mixing bags leak?—have already been answered. That being said, there are some challenges to implementation.
Product compatibility is one issue. Determining suitability is likely to require new procedures that are outside of the parameters of current stability testing. Organizational resources will be challenged to do appropriate testing and provide answers quickly in order to demonstrate suitability for the application.
Because it involves a greater change than simply moving a production line from one building to another, switching to SUDS also requires applying more QA and regulatory resources earlier than usual in the project. QA and regulatory staff must be available—often on a full-time basis—to audit suppliers and determine how the move to SUDS will impact documentation packages and affect filing requirements. As noted above, most vendors can supply baseline validation packages to help support this effort.
When considering the business case for SUDS, it helps to take a broad view. Various vendors' analyses have ranged from 50% reductions in operating costs to none. Disposable components are an ongoing expense that will impact the production budget. On the other hand, the savings to be gained through greater process efficiency are significant, and shaving weeks off the project timeline is a huge gain.
There are also utility savings. And although it is difficult to quantify, the value of decreasing the risk of cross-contamination could be enormous.
Proven in various phases of pharmaceutical development, SUDS is proven technology that offers several benefits for aseptic manufacturing. Compared to reusable equipment, SUDS allows the manufacturer to allot less space for washing and sterilizing equipment and for staging parts, and it simplifies management of components and parts. SUDS can help a manufacturer reduce clean utility consumption and possibly reduce operating costs as well. Decontamination is simplified, and personnel and equipment flows within the facility are streamlined. Manufacturers who begin exploring SUDS options now will be ready when clients start requesting the capability.
Robert L. Roy, PE, is a senior consultant at Integrated Project Services (IPS), a full-service engineering, construction and commissioning & qualification company headquartered in Lafayette Hill, PA. He can be reached at firstname.lastname@example.org.
Jason S. Collins, RA, NCARB is a senior process architect at IPS. He can be reached at email@example.com.