Harnessing The Advantages Of Single-Use Systems

This article is part of a special feature on single-use systems that was published in the October issue of PTE Digital, available at http://www.pharmtech.com/ptedigital1010.

There are several key advantages that single-use systems offer over conventional stainless steel equipment. Some of the most important include:

• No cleaning and associated cleaning validation — although process validation and process equipment qualification remain unchanged.
• Single-use systems arrive gamma sterilised and are pre-qualified by the supplier.
• The risk of cross contamination is mitigated.
• Faster changeover campaigns for batch-to-batch and product-to-product.

• Lower capital investments in facility due to reduction in utility requirements, downsizing of cleanroom area and reduction in overall facility footprint.
• Increase in overall equipment efficiency.
• Opportunity to defer capital investments to operational expenditures by using a pay-upon-use model.

The extent to which the above advantages can be harnessed, however, is predicated on the infrastructure and stage of a given pharmaceutical manufacturer. If a manufacturer devotes their technical feasibility resources towards the sole adoption of single-use systems implementation in a new facility, then they will realise all of the advantages, but in reality most manufacturers tend to employ hybrid manufacturing models that incorporate both single-use and conventional technologies. In part, this is due to existing manufacturing infrastructure or technical feasibility gaps that cannot yet be fully overcome with single-use systems — whether they are limitations in scale or limitations in underlying technology.

Christian Julien. One-Touch Single-Use Systems, Business Development Manager, at Meissner Filtration Products.

Overcoming challenges

Single‑use systems also impose challenges. One of the most prominent issues is supplier dependency. For example, the sterilisation validation is de facto outsourced to the supplier; this in and of itself will warrant a thorough supplier quality audit. Because of the sheer number of combinations and permutations of single‑use systems that can be conceived to cater to the often very specific process needs of end users, providing a gamma dose report is insufficient to substantiate a sterility claim. Instead, end users need to verify if the supplier has established an appropriate methodology under ANSI/AAMI/ISO 11137 that encompasses all the components in the single‑use system. The evaluation of supplier quality systems, review of component and system qualifications, and assessment of suppliers’ expertise and capabilities are standard within the scope of a supplier audit.

In the end, for much of the same reasons that manufacturers have adopted a risk mitigation strategy by having at least two suppliers (e.g., for filters and critical raw materials), the same strategy is being pursued towards single-use suppliers. The proprietary nature of unique single-use components, however, adds an extra layer of complexity as the licensing of proprietary technology is not always feasible, which precludes second‑sourcing.

Other challenges to the adoption of single‑use systems are mainly based on technical merit and feasibility or predicated on size; for example, the maximum capacity for a single‑use bioreactor is 2000 L. These factors are indicative of the current state of single‑use technology, which is evolving rapidly, and what could be identified as a feasibility gap today may very well be overcome in the near future. Suppliers are eager to deliver on the ultimate premise of a fully single‑use manufacturing platform. Their quest to deliver on this premise, however, often leaves implementation questions to be answered by end users, who must usually prominently rely on cross-functional expert teams dedicated to evaluating the feasibility of single‑use system components and subsystems using a more holistic approach.

Biopharma, as a subset of the pharmaceutical industry, has been an early adopter of single‑use systems. This is, in part, due to the compatibility of the biological manufacturing processes, which are largely aqueous based, with current single-use materials technology. In contrast, the pharmaceutical industry, which predominantly uses chemical synthesis, has not been able to implement single-use systems as readily because of inherent solvent compatibility challenges with first-generation product contact materials such as polyethylene, which is predominantly used in biocontainers. The challenges with respect to reaction conditions remain largely unaddressed, although the issue of inherent material incompatibility is now being mitigated somewhat with the development of more chemically resistant product contact materials, such as PVDF (polyvinylidenefluoride).

We have recently introduced PVDF‑based biocontainers (FluoroFlex) that are now under evaluation for antibody drug conjugates manufacturing processes where the final linkage steps between an antibody and a small molecule require solvent compatibility beyond that which can be achieved with polyethylene biocontainers. A continual materials science approach and expert knowledge in polymer technology is essential to address these fundamental challenges and to propel the adoption of single‑use technology into the pharmaceutical industry at large.

Environmental and regulatory concerns

Many people expect environmental and regulatory issues to be the primary hurdles to the implementation of single-use systems in the pharma industry. However, the biopharm industry has been able to successfully overcome these challenges — although it admittedly started to adopt single‑use platforms more than 15 years ago. In the end, every organisation will have to conduct a technical feasibility and cost‑of‑goods‑manufactured exercise to determine what they can gain by utilising single-use systems. It should be kept in mind, however, that this analysis will always be based on the current state of technology and the fact that single-use technologies are evolving so rapidly (e.g., adoption and integration into isolator technology) they should also be considered.

Manufacturers will also need to conduct cost comparisons between single-use and conventional non-disposable systems, or a combination of both, in order to find the best option. There are situations where each manufacturing approach has its own merit and, undoubtedly, situations where the marriage of both technologies provides the highest economic benefit. A safe haven for single‑use technology often revolves around media and buffer preparation applications, with most published economic studies showing a rather consistent advantage for single‑use implementation (B. Barnoon and B. Bader, BioPharm International Supplements, 2008). Aside from liquid management for process fluids or even drug product, the economic benefits for a single‑use option can only be assessed based on a clear understanding of the manufacturing process at hand and by following a systematic approach, including a thorough technical feasibility assessment, and a process and product risk analysis in light of acceptable process control and logistics strategies.

The evolution of technology

Single‑use filter capsules could be seen as one of the early precursors of single‑use systems as they have long been implemented as stand‑alone products. Today, they more prominently take on the role of a component (albeit a critical one) in the context of an entire single‑use system implementation, which can vary from a simple sterile filtration into a collection biocontainer, to ever more complex fluid paths with multi functionality, such as those deployed in filling applications.

During the next few years, one of the most important trends in the evolution of single‑use systems implementation will likely be the integration of fluid management systems and single‑use unit processing operations. This will make single-use adoption technically more challenging because the risk complexity increases proportionally to the enhanced functionality. At the same time, however, it will also provide the opportunity for process streamlining and the promise of further economic benefits. The extent to which the industry is able to standardise on such platforms and whether the added complexity is truly warranted will need to follow a risk‑based manufacturing approach. Ultimately, the implementation of such systems will be derived from the industry market drivers themselves such as the need to use manufacturing innovation as a means for cost control.

www.meissner.com