Single-Use Technology

A Practical Guide to Design and Implementation

Adriana G. Lopes, Andrew Brown

• Editorial: De Gruyter
• Año: 2019
• ISBN:
  9783110640670
• Edición: 1
• Categoría: Scienze fisiche
• Categoría: Chimica industriale e tecnica

Single-Use Technology (SUT) is the first comprehensive publication of practical considerations for each stage of the implementation process of SUT, and covers the selection, specification, design and qualification of systems to meet end-user requirements.

Having become readily available for all processing operations within the biopharmaceutical industry, SUT has the potential to reduce capital costs, improve plant throughput and reduce the risk of cross-contamination. However, there are no clear guidelines to aid the end-user on implementation of these technologies into a validated, good manufacturing practice (GMP) environment.

This book presents approaches for the implementation within various end-user facilities and systems, SUT within regulatory frameworks (ICH Q8, Q9, Q10 and GMP), standardisation and assessment strategies, specifation of user requirements and SUT design, risk assessment and evaluation as well as qualification for different SUT types.

1Introduction

Recent trends in the biopharmaceutical industry derived from technological advances (e.g., increased drug potency and smaller niche markets targeting patient-specific drugs) have resulted in the need for flexible manufacturing facilities. Further achievements in engineering cell lines capable of high production titres has led to a decrease in the volumetric manufacturing capacity needed to align with market requirements. Concurrently, the previous decade has seen the development of single-use technologies (SUT) applicable to biopharmaceutical manufacturing from the simplest and widely used bag systems and filters to more complex systems such as bioreactors, chromatography and fill-finish operations. As a result, industrial adoption of SUT has increased gradually, and end-users are considering application of the technology to operations discounted previously due to technical or scale limitations. Increased adoption of SUT has also brought about the realisation that new challenges are encountered to select, specify, implement and maintain the technology throughout the lifecycle of the active pharmaceutical ingredient (API). This handbook has been written to provide practical guidance on: (i) considerations for the end-user to review while choosing technologies to apply to processes; and (ii) implementation of SUT.

The route by which a process for the manufacture of biological products is designed, implemented and qualified can be long and complex. It requires the input of multi-disciplinary teams and there are many risks of failure. For example, the process can fail if it cannot be controlled to provide reliable batch-to-batch consistency of the product with sufficient quality. Exposure to risks by a particular organisations is dependent upon its experience with the product, process, manufacturing technologies and scale of operation. Many single-use systems are considered to be ‘mature’ because they have been present on the market for >10 years, been through design changes to improve performance, and have been utilised across a wide range of scales and manufacturing scenarios, from clinical through to commercial. However, other SUT are ‘immature’ and require more time to implement due to limited knowledge, availability and adaptability of the technology. There are no standardised approaches for SUT implementation. Instead, the implementation strategy should be ‘tailored’ based upon the type of technology and level of expertise of the end-user.

Compared with traditional stainless-steel systems, additional risks must be considered when using SUT. A comprehensive list of these risks is shown in Table 1.1. They have been grouped based upon impact to the end-user, supply chain, material and process.

These risks illustrate the range of capabilities that end-users must possess within their organisation, or that they will need to leverage from the supplier or third-part service providers to implement SUT. Hence, some end-users continue to employ traditional stainless-steel systems that they have expertise with, or adopt a ‘hybrid’ approach whereby implementation of SUT is used to support process operations that use stainless-steel tanks (e.g., media/buffer preparation, hold, addition or waste collection). However, irrespective of whether the SUT is adopted fully or partially, the end-user should develop a robust implementation strategy so that risks are detected and mitigated in a timely manner.

Table 1.1: Risks involved in adoption and use of SUT.

There are many similarities between a project to implement a SUT and the traditional design approach for a stainless-steel system. However, there are differences, particularly in relation to the timing of when decisions are made and the criteria that are assessed. An overview of the key phases for implementation of SUT is laid out in Figure 1.1. An implementation plan should be developed at the start of the project and updated as progress is made, and a better understanding of the technology is developed. The end-user should start with assessment of the feasibility to use the SUT system for a given application, which should include technical and business assessments of the technology. Selection of an available supplier of SUT should be evaluated concurrently. Depending upon the complexity of the SUT for a given application, or maturity of the system, trial of a given system may be necessary before the technical feasibility can be completed. This strategy requires the co-operation of the SUT supplier, but should start with the end-user specifying the requirements of the system, including how it integrates with the wider process and facilities. At the end of the feasibility assessment, a decision to proceed with a preferred supplier is made. Hence, investigation of the quality and robustness of the supply chain of the supplier should be considered as part of this selection process. Once selected, the implementation plan should be updated when better understanding of regulatory acceptance of the SUT, system reliability and, above all, the resulting impact upon the quality of the product is known. A process-control strategy is required to ensure measurement of product quality, process interaction and validation. This strategy should underline the level of acceptable risk to the API in terms of cross-contamination, adsorption, and extractables/leachables from the SUT material that is product contacting, as well as process risks in terms of system integrity, process adjustments and operator safety. Specification, design and validation should ensure that the SUT system is fit for purpose so that, once implemented, it continues to support continued manufacture of the API to the required quality level. Once validated and in use, performance of the SUT should be monitored with metrics fed back to the supplier to ensure that issues are identified and dealt with in a timely manner.

Figure 1.1: Key focus areas during SUT implementation.

1.1Benefits and limitations of single-use technology

As the biopharmaceutical industry matures, the trends are towards the higher flexibility and responsiveness of production facilities as well as reduction of manufacturing costs and timelines in a background of increasingly strict regulatory and capacity demands. SUT can support an end-user to benefit from these trends but limitations do exist with the technology.

1.1.1Improved process flexibility

By decoupling the process train from the facility infrastructure and transforming the facility into separate individual workstations it becomes easier to reconfigure the facility to meet changes in product scale or the type and number of products to be manufactured. The end result is greater flexibility with regard to the process and product. The portability of the equipment means that manufacturing spaces can be re-purposed as required. In addition, capacity can be increased through scale-up or scale-out, with minimal or zero impact to support systems such as water-for-injection (WFI) or generation of clean steam. As a result, SUT enables the drug manufacturer to increase manufacturing capacity and/or respond rapidly to market demands. If product demand increases, rapid expansion of capacity can be achieved by adding together similar SUT units with no need for implementation of process changes or improvements [1].

Single-use systems provide easier handling and quick turnaround times between batches and manufacturing campaigns due to the removal of clean-in-place (CIP), sterilisation and re-qualification activities [2]. This strategy improves process flexibility, and is particularly useful for multi-product facilities where assurance is required that the equipment is cleaned appropriately between batches of different products.

1.1.2Increased speed of implementation

Faster construction, commissioning and launch of facilities can be achieved by using SUT. This is driven by the reduction in complexity of secondary support systems that would otherwise lead to longer design, fabrication and qualification activities. Single-use systems save time and money due to rapid product change-over and associated validation studies with minimal risk to product integrity, and results in accelerated time to market [3]. It also means that capital decisions can be delayed without impacting timelines for drug development. This approach reduces the risk that a decision to build a facility is taken when the capacity required is unclear or likely to change. If a manufacturer of a drug for clinical trials requires to build a clinical facility, SUT is much faster to implement than a traditional stainless-steel facility. Also, the overall costs of implementation are lower so, if the drug fails clinical trials, it carries a reduced risk to the business due to the flexibility of re-configuration to a new product and reduced capital costs.

1.1.3Cost savings

sually, single-use systems are supplied pre-sterilised (by gamma radiation), thereby eliminating the need for CIP or steam-in-place (SIP) support systems, areas and procedures, as well as the equipment maintenance associated with these practices [4]. Reduction of capital investment costs for process equipment is achieved by elimination of utility requirements for CIP and SIP capabilities, and reduction of the number and size of CIP skids [2, 5]. Due to elimination or reduction of CIP and SIP requirements, generation of purified water (PW) can also be reduced in scale and cost for new-build facilities.

SUT also results in better utilisation of facility assets. The reduced scale of SUT equipment (smaller facility footprint) results in reduced fixed costs (e.g. investment, operation, maintenance) and a ‘better utilised facility’ that can respond to higher demands in production by process intensification.

1.1.4Increased product safety

Single-use operations result in a reduced risk of cross-contamination and increased assurance of sterility [6] due to elimination of cleaning between batches and the associated validation. The low detection limit assays used to measure contaminant...