The manufacture of sterile pharmaceuticals is conducted under current good manufacturing practice (cGMP). Depending on the complexity of the process, manufacturing involves multiple unit operations for upstream production and downstream product formulation. The processing of sterile pharmaceuticals takes place within cleanrooms and, in line with such controlled environments, measures are taken to minimise the possibility of the product from becoming contaminated with micro-organisms.
Until recently, most of the equipment used for manufacturing was sterilised within the production facility and reusable. The most common material was stainless steel. The past few years have seen the introduction and application of single-use technology.
Single-use, sterile disposable technologies (also referred to as biodisposable technologies or SUTs) are available in many formats and confer various advantages for pharmaceutical manufacturers. They comprise products generally manufactured from plastic polymers via the processes of injection moulding, extruding and blow moulding.1
The plastic moulding process means that many different designs are available and that systems can be suitable for many different processes, including niche and small batch products. Such technologies include tubing, capsule filters, single-use ion exchange membrane chromatography devices, single-use mixers, bioreactors, product-holding sterile bags in place of stainless steel vessels (sterile fluid containment bags), connection devices and sampling receptacles.
Single-use disposable items are most commonly used in aseptic processing as a contamination control measure. The applications include devices for making aseptic connections, sampling devices, mixing devices, product-hold bags and disposable manifold systems.
It is important that during validation of the sterilisation process the integrity of the plastic material is examined for deformities or to see if it has become brittle
In terms of rendering the single-use system sterile, because plastics cannot be subjected to heat sterilisation, the primary way in which plastic disposable devices are sterilised is by either gamma irradiation (electromagnetic irradiation), electron beam or by using ethylene oxide.2 Of these different sterilisation methods, gamma radiation is the most widely used. It is important that during validation of the sterilisation process the integrity of the plastic material is examined for deformities or to see if it has become brittle.
Single-use technology began with the use of membrane filters, which were introduced into biopharmaceutical processing in the 1970s. However, further innovations were slow to develop and until recently production facilities relied on the use of relatively inflexible, hard-piped equipment including large stainless steel bioreactors and tanks to hold product intermediates and buffers. From the mid-2000s, however, the use of sterile disposable SUTs has become more widespread.
Over the past few years there has been a trend towards the adoption of SUTs across the manufacturing process. The drivers for the adoption of disposable technology include the need to reduce both power consumption and process downtime.3 A further, important reason is increased contamination control.
The development of single-use technology has been aided by technical advances. However, there are several aspects of the technology that require further improvement and are continually evolving, meaning that few processes can be designed around SUTs alone.4
There are several aspects of the technology that require further improvement and are continually evolving
Of the various applications of single-use devices, the adoption of SUTs for aseptic connections is arguably the most advantageous. Types of aseptic connections include the connection of a vessel or filter to another item of equipment for the transfer of fluids. Conventional methods of connection involve steps such as clamping or heat welding of tubing. The major risks arising from this stem from the external environment and from any microbial contamination that could be transferred from the operator. Innovations in aseptic connection technology have led to the development of single-use connector systems to allow for a totally enclosed and automated process. These are based on the so-termed alpha-beta principle, which allows the connection to be performed in an environment that does not require unidirectional airflow cabinets or other equipment to maintain asepsis.
A second innovation of importance involves biocontainer bags to hold product. In line with advances with aseptic connections, there is a drive towards the adoption of disposable bag technologies in biopharmaceutical production and away from fixed, stainless-steel equipment, which requires more complex engineering configuration and far more components in terms of separative valves and piping.
The common configuration of product holding bags is as single-use assemblies consisting of either two or three dimensional bags connected to a manifold of tubing, connectors and filters. The design is such that no part of the equipment will have direct contact with the product unless the component or part of the equipment is also sterile, single-use and maintains the sterile liquid pathway of the closed system assembly.
Advantages of single-use
SUTs can offer significant advantages over standard reusable stainless steel systems,5 including:
- Reducing the risk of microbial contamination. SUTs are sterilised using gamma radiation, a process that has proven lethality. A further advantage is that the design of the systems means that opportunities for micro-organisms carried in cleanroom air or those that could potentially be deposited by the operators are significantly reduced. This enhanced protection includes reducing the point of contact between the operator and the sterile part of the equipment: an example here is with the use of sterile connectors, which are designed to prevent the operator from directly touching the sterile area. Furthermore, the sterilisation methods used for SUT (primarily gamma radiation) present a low risk of sterility cycle failure compared with autoclaving. Because each item is discarded after its single-use, the risk of batch cross contamination or product carry-over is eliminated.
- Cleaning and associated cleaning validation are not required. Cleaning validation can be a complex and time-consuming process, especially where a vessel is used for different product streams where it must be demonstrated that no residues of the previous product remain.
- Labour costs are generally lower because fewer resources are required for the disassembly, cleaning, reassembly and autoclaving of equipment. There can also be a reduced requirement for QC testing.
- Energy costs are lower in terms of the power, water and cleaning chemicals needed for Clean-in-Place/Steam-in-Place systems.
- Space savings. Single-use systems can have a smaller footprint and new systems do not need to be stored in the process area (unlike large vessels or reactors). Furthermore, being disposable, once the system has been used it can be removed from the process area.
- Process efficiencies are arguably greater because turnaround times are substantially reduced (through the elimination of the need to clean and to sterilise equipment). Other process efficiencies relate to portability, scalability, and facility operations management.
- Capital investment. The purchasing and design of large vessels for processing is generally far more expensive compared with single-use disposable systems. Capital investment relates to both equipment (such as vessels) and supporting infrastructure. Furthermore, many single-use systems can be purchased direct from a supplier, whereas the manufacture of large items of equipment is rate limited by long lead times.
In applications where hazardous materials are being processed, such as cytotoxic drugs or potent biological materials, closed single-use systems offer additional protection to operators by isolating them from the hazards.
Regulatory perspectives
SUT innovation fits well with the Quality by Design (QbD) concept and related initiatives by regulatory authorities, such as the US Food and Drug Administration and with EU GMP practices. The focus of this concept is that quality should be built into a product with a thorough understanding of the product and process by which it is developed and manufactured along with a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks.
In summary, single-use systems are becoming more commonplace in cleanrooms, especially those for the production of sterile products. When used with a cleanroom, single-use products provide a robust means of reducing microbial contamination. SUTs also present a number of advantages in terms of reduced energy and labour costs, as well as allowing for faster turn-around times.
There are some disadvantages with SUTs. These include the relatively high costs of individual items, although this tends to be off-set over time once the capital costs of stainless items are tallied with the energy costs required for their cleaning. Another disadvantage is that not all pharmaceutical processes are able to make the transition, especially more specialised areas of manufacturing. Nevertheless, as advances in the development of single-use systems continue, the wider their application will become.
References
1. Sandle, T. and Saghee, M. R. (2011): Some considerations for the implementation of disposable technology and single-use systems in biopharmaceuticals, Journal of Commercial Biotechnology, Vol. 17, No. 4: 319–329
2. Cleland, M. R., O’Neill, M. T., and Thompson, C. C. (1993). “Sterilisation with Accelerated Electrons,” in Morrissey, R. F. (Ed.). Sterilisation Technology: A Practical Guide for Manufacturers and Users of Health Care Products, Van Nostrand Reinhold: New York
3. Rao, G., Moreira, A. and Brorson K. (2009). Disposable bioprocessing: the future has arrived, Biotechnol Bioeng. 102(2):348–56
4. Shukla, A.A. and Gottschalk, U. (2013). Single-use disposable technologies for biopharmaceutical manufacturing, Trends Biotechnol. 31(3):147–54
5. Samavedam, R.; Goldstein, A. and Schieche, D. (2006). Implementation of disposables: Validation and other considerations. Am. Pharm. Rev., 9 (September/October): 46 –51
More on this topic is available in Tim Sandle’s book ‘Sterility, sterilisation and sterility assurance for pharmaceuticals’. For details visit www.woodheadpublishing.com/9781907568381
