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Frequently asked questions on implementing and using single-use technologies
Today, nearly 97% of biopharmaceutical manufacturers use single-use technologies.1 Not only are manufacturers implementing single-use technologies, but also the range of applications for which these technologies are being used is expanding. Single-use technologies are now being implemented for critical steps involving direct product contact. This gives new importance to the way these technologies are selected, implemented, and used. Issues of qualification, validation, and sterilization have greater implication when entire product batches are at stake.
The following are answers to several questions that broadening implementation of single-use technologies has raised among biopharmaceutical manufacturers. These questions and answers also provide an accurate view of the limits and benefits of single-use processing, and insight into the future direction of this processing paradigm.
HÃ©lÃ¨ne Pora, PhD
Q Where are single-use technologies currently being used in biopharmaceutical processing?
A Single-use technologies have traditionally been used for small-scale buffer filtration, media preparation, and storage. Recent innovations have made a wider range of single-use technologies available for most downstream purification applications and production scales. These include mixing technologies, cell culture bioreactors, membrane and column chromatography, tangential flow filtration systems, and formulation and filling technologies.
Q What are the limits in scale of operation?
A Single-use technologies are now common in full-scale production operations, and range in size from just a few milliliters to several thousand liters. Disposable bioprocess bags can accommodate up to approximately 3,000 L of fluid and disposable bioreactors have been used for production purposes up to 500 L of cell culture.
Although not all single-use technologies are fully scaleable, a growing number are being introduced for use in commercial production. Advances in disposable membrane chromatography are pushing this technology beyond pilot-scale applications into commercial production. Even at commercial scale, however, single-use technologies may have capacity limitations. The 3,000–L bioprocess bags are one example. As non-rigid containers, both their integrity and ability to be handled beyond this size come into question.
Q What are the limits of operating pressure and temperature associated with single-use systems?
A Single-use systems can withstand comparatively less pressure than stainless steel systems. However, exact limits depend on the material composition of the system and the tubing attachment method. In general, bioprocess bags and tubing cannot withstand more than a few psi (<0.5 bar) of pressure. However, tubing can be reinforced to withstand greater pressures. Most capsule filters can be used with up to 45 psi (3 bar) pressure and a limited few can withstand up to 90 psi (6.5 bar) pressure.
Liquid generally moves through single-use systems by way of gravity, but in some cases a peristaltic pump is also used. Although operating pressure limits do not impact processing performance, there is a certain resistance to change in the biopharmaceutical industry that can make addressing pressure differences more difficult.
Biopharmaceutical manufacturers also must consider the temperature limits of single-use technologies when selecting new components and systems. Disposable components are generally suitable for standard biopharmaceutical operating temperatures, which range between 4 and 40 °C. However, some bags, tubing, and connectors may not meet low temperature requirements for storage. Most biopharmaceutical drugs are stored at –30 °C but some products (e.g., cells) require storage at –80 °C. It is critical that biopharmaceutical manufacturers validate all components in the assembly to ensure that they meet the complete range of temperature requirements. Although stainless steel systems have no temperature limitations, integral parts such as seals often do, and therefore must be validated to temperature specifications.
Q Have sterilization methods for disposables and single-use systems changed in recent years?
A No. Gamma irradiation is still the most common sterilization method for disposables and will continue to be, because gamma irradiated single-use systems are supplied to the end user pre-assembled and pre-sterilized. This reduces labor, especially as systems grow more complex. Most disposable components also can be autoclaved with the exception of bioprocess bags. Steam sterilization is not suitable for single-use technologies. However, a few filter types can withstand this method of sterilization.
Table 1. Operating scale of single-use technologies
Q What type of documentation is provided to demonstrate that systems have been irradiated at the right dosage?
A The irradiation company provides a certificate of irradiation to demonstrate that the single-use system has been irradiated to dose- range specifications. If any aspect of the single-use system is changed, including size, density, thickness, packaging, etc., it is critical that dose mapping be performed again to the exact specifications of the modified single-use system and its package. Dose mapping ensures that the level of irradiation falls within the appropriate window of irradiation for each component within the disposable assembly. Although the irradiation range varies from system to system, the usual gamma irradiation dose for any single-use system is typically a minimum of 25 kiloGrey (kGy) and the maximum is 50 kGy.
Q What is the difference between extractables and leachables?
A By definition, extractables are potential solutes derived under worst-case conditions from the drug product or process fluid contact materials, typically using model solvents. Leachables comprise the subset of contact material solutes detectable in actual product or process fluids. Leachables may also be generated through the interaction of products and contact materials over time. Solvent and temperature conditions, among other factors, determine whether extractables or leachables are generated. Extractables represent the potential for soluble materials to leach from the disposable component under extreme testing methods, but would not otherwise be released into the product during normal processing. By contrast, leachables, which are drug product or process fluid-specific, are released into the product under normal processing conditions.
Since leachables pose an inherent contamination threat, the single-use industry generally uses the term "extractables" when describing soluble materials that could be released from a disposable component. It is important to note that there will always be some level of extractables present. The goal of extractables testing is not to demonstrate their absence, but to make sure that they will not adversely impact the quality, safety, or stability of the drug.
Q What are the common methods for testing extractables?
A A wide range of tests can be performed to assess and characterize extractables. Factors determining extractables include the materials used, attributes of the solvent, and processing conditions such as time, temperature, and sterilization. Thermodynamic properties, including the solubility, diffusion rate, and degradation rate of processing materials, also play a role.
Although the results of many of these tests are provided in documentation from the supplier, additional testing may need to be performed by or requisitioned by the end user. This depends on the criticality of the application and the manufacturer's specific knowledge of the product. For example, manufacturers may want to do some specific product validation testing for formulation and filling applications to demonstrate to the FDA that proper toxicity studies have been performed. Manufacturers can turn to process integration companies, including disposable equipment suppliers, to perform these studies.
Q Do I need to perform these studies for each single-use system?
A No. It would depend on the criticality of the application and the level of existing validation information data for each single-use component. It is recommended that end users work with the system integrator to determine whether a process specific study is required. Following are recommendations for performing extractables studies on filters, bags, and integrated systems:
When validating disposable filters, processors must first quantify the materials extracted from a pre-sterilized unit by measuring the nonvolatile residue, or the chemicals extracted from the test sample. Then, the unique footprint of the extracted material should be analyzed through infrared spectrum or Fourier Transform Infrared (FTIR) spectroscopy. Liquid or gas chromatography and mass spectroscopy are more sensitive methods of identifying semivolatile compounds, but are not typically applied in generic filter studies.
The process for testing disposable bags is similar to testing filters, but there are some important differences, including consideration of the bags' integrity and tensile strength. Physiochemical tests for disposable bags used in drug processing seek to characterize the nonvolatile residue; residue on ignition (inorganic residue); the presence and type of heavy metals; and the buffering capacity, or the estimated strength of the buffering effect caused by extractable chemicals. All disposable materials used should meet the requirements of the United States Pharmacopeia or the European Pharmacopoeia upon manufacture and also over their lifecycle.
In any testing program, it is important to look at the whole system, taking into account potential interactions over time and through all the steps of a dynamic manufacturing process. For example, consider the length of time that a product is in contact with various components of the system. This is especially important when using disposable bag systems for filtration and storage. Generally, as the period of contact lengthens, the potential for leachables to appear becomes greater. Also, consider the ratio of the product volume to the surface area of various components: the greater the surface area, the greater the potential for the creation of extractables.
Q Are there any standards applicable to extractables studies?
A Although standards for extractables testing do not exist today, the industry is working through the Bio-Process Systems Alliance (BPSA) to establish guidelines for selecting, using, and disposing of single-use technologies. The goal of BPSA is to promote confidence in the application of single-use technologies in the biotech and biopharmaceutical manufacturing industry. The organization comprises leading companies engaged in the manufacture and testing of single-use technologies.
Q I am currently using a stainless steel assembly. What qualification work would I need to perform if I were to use a single-use system?
A Just as for stainless steel equipment, the qualification of single-use systems requires that manufacturers verify that every aspect of the system is performing as intended. The difference between qualifying single-use systems and stainless steel equipment is the hastened timeline. Since single-use systems are installed in as few as four to six weeks, processors must be prepared to conduct qualification studies in a very short time.
Q How long does it typically take to get a single-use system into operation?
A Single-use systems can be installed in just a few weeks—approximately three to four times faster than stainless steel systems. This makes single-use systems especially useful for production of "fast track" drugs and at development scale, where flexibility, speed of installation, and safety are critical. Particularly with clinical batches of investigational drugs, elimination of equipment cleaning by using single-use systems greatly reduces the risk of cross-contamination. However, as with any system, getting all parties to agree on the design can be one of the most time-consuming steps, along with sourcing all of the components.
Q What are the lesser-known advantages of single-use processing?
A Seemingly unimportant characteristics of single-use technologies can add up to significant time and labor savings. For example, single-use systems have clear tubing and clear or translucent capsule filter housings, which enable operators to observe fluid levels and flow. This allows fluid discoloration and air pockets to be readily detected, so that problem areas can be immediately identified and isolated from the rest of the process. Single-use technologies can also be supplied pre-assembled and pre-sterilized to significantly reduce setup time.
Reduced capital costs, faster installation, and the smaller footprint of single-use systems as compared to stainless steel equipment have helped make in-house production feasible for many biotechnology companies. These benefits also provide significant cost-savings for large drug companies and contract manufacturers.
Hélène Pora, PhD, is the marketing director at Pall Life Sciences, Pall France, Saint Germain-en-Laye Cedex-France, +126.96.36.199.32.20, firstname.lastname@example.org
1. BioPlan Associates. Third annual report on biopharmaceutical manufacturing capacity and production. 2005 Jun. Cited in Brown A. Chem Processing. Disposable equipment makes lasting gains. 2006. www.chemicalprocessing.com/articles/2006/017.html.