Achieving Lean Processing With Single-Use Systems

Single-use filtration and fill–finish technologies can be used as part of a lean manufacturing strategy to boost production, and reduce manufacturing waste and costs.

Single-use manufacturing solutions can accelerate production, improve flexibility, and reduce costs and waste–benefits that are well-aligned with lean process initiatives. Based on principles largely developed by Toyota, lean manufacturing seeks to identify and eliminate waste in manufacturing processes to reduce the cost of bringing a product to market (1). Focusing on creating more value with less work, lean manufacturing generally focuses on reducing eight specified wastes (see Table 1).

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Implementing single-use filtration and fill–finish systems can deliver lean process improvement efficiencies and eliminate waste from the manufacturing workflow. Single-use systems can speed up production processes, reduce the risk of deviations, maintain consistency and have a positive impact on the bottom-line.

Table 1: Eight types of wastes targeted by lean process initiatives.

Delivering value with single-use filtration

Single-use filtration systems can deliver value in a number of ways. However, it is particularly beneficial if the single-use system has a modular structure that is replicable and scalable across different geographies, as this means the filtration assembly can keep pace with changing product, scale and site requirements.

Lean processing

As will be demonstrated later in a fill–finish case study, single-use assemblies can reduce processing time by as much as 50% through decreased preparation and set-up times. A number of elements drive these reductions, such as:

• modular manifold designs mean they can be built on site and scaled as required

• bags can be designed such that filling processes eliminate the need for operator handling

• sterile filtration assemblies can facilitate technology transfer between early development, late development and commercial manufacturing

• innovations in disconnection technology can reduce the time required to make sterile disconnection compared with the time taken by traditional tube sealers.

Before implementing single-use technologies, a thorough assessment of the current processes and opportunities for improvement should be conducted and objectives should be clearly defined. It is also important to pilot solutions and conduct performance testing in a laboratory setting before a definitive solution is finalised. Technology experts should also review process parameters, such as flow rate and pressuredrop requirements, and recommend the appropriate filter membrane and size when designing filtration subassemblies. Hands-on testing prior to installation will also give operators a greater degree of confidence than a typical new processing setup might usually foster, and will also give them the opportunity for real-time feedback, which will enable the solution to be better adapted to their actual process.

The effectiveness of the technologytransfer process is critical to maintaining product quality and decreasing time-to-market. Using different systems from different vendors can impede transfer and force processes developed at one scale to be recreated and re-optimised at other scales; for example, a vendor may not be able to offer its solution at all scales from process development to manufacturing, in which case the client would be forced to buy products and technologies from multiple vendors that may not be fully compatible with one another. Differences in product claims and shelf life from multiple vendors can also impact the implementation of single-use technology during technology transfer.

Using replicable, modular single-use systems, however, can facilitate cost-effective and timely technology transfer across multiple sites and different scales because the same product technology platform, same contact materials and product claims make the qualification process easier.

Impact on the bottom line

Single-use systems can reduce materials usage by as much as 20%. They can also reduce the number of parts that need to be maintained. With each new catalog number incurring a cost of up to approximately €837 to maintain it annually in an ERP system, the reduction represents an important cost saving.

Optimising tangential flow filtration

Tangential flow filtration (TFF) can rapidly and effectively separate and purify biomolecules. Employing single-use systems in this area can improve product yield, quality and purity. The first step in TFF process development is to define what the process must achieve and what goals must be met. Understanding these objectives will aid selection of the appropriate unit operation and operating parameters. Important process objectives to define are:

• final product concentration

• feed volume reduction

• extent of buffer exchange

• contaminant removal specification.

Next, it is important to identify and quantify any criteria by which the success of the operation will be measured. The primary goals for successful protein processing are:

• high product yield

• high product quality (or activity)

• high product purity

• controlled bioburden and endotoxin.

The process should also scale up accurately, enable straightforward validation and be robust during continued use at industrial scale. Finally, the economic objectives for the process must be met and constraints such as process time, unit operation size, or buffer use must be observed.

Once TFF processing is complete, all of the product must be removed from the system. There are several factors that can contribute to an optimised productrecovery strategy including:

• lines should slope to a low-point recovery port

• the tank, with a sloped bottom, should be mounted above the feed pump

• a high-point air port for blowdown low pressure (~ 5 psig) should be included

• a retentate-line buffer entry for buffer displacement should be included.

Product recovery will also be simpler from systems with a low minimum working volume because more product can be pumped out of the recycle tank, and there will be less volume throughout the lines and membranes. The minimum volume at which the system can operate must take into account the required process flow rate, and avoid causing significant turbulence or any air entrapment in the process fluid. It must also account for volume in the piping, valves, instruments, membranes and some minimal volume in the recycle tank.

High quality and purity

To ensure high product quality, the TFF system should be designed to avoid air–liquid interfaces and vortexing in the recycle tank, which can damage proteins. Vortexing can be reduced with proper agitator placement and design, and use of a vortex breaker at the tank outlet. Additionally, a sub-surface retentate return to the recycle tank that minimises turbulence will prevent air entrainment. Careful feed pump selection can also help protect product quality by eliminating cavitation.

The system must be designed to maximise removal of contaminants during diafiltration, sanitising and flushing to ensure high-product purity. Product purity is enhanced by minimising dead legs and contamination points, and avoiding flexible lines that are longer than necessary. A well-mixed process stream is also critical, and depends on agitator design and placement for mixing at all volumes, a retentate dip tube return designed to avoid short-circuiting, and a diafiltration bufferstream entry on the retentate line.

Impact of single-use on fill–finish

Traditional fill–finish systems are fixed systems that use complex component assemblies requiring operation and cleaning in a controlled, aseptic environment, using CIP/SIP, time pressure and piston pumps for operation. This presents a number of challenges resulting from stringent requirements for flowpath integrity and sterility, operational safety and efficiency, and fill accuracy. Because of the intensive use of stainless steel components, traditional fill–finish facilities are considered inflexible, with long change-out times and high operating costs because of CIP, SIP, labour and facility costs.

Case study

A single-use fill–finish solution (Mobius, Merck Millipore) was implemented by a pandemic flu vaccine manufacturer at an existing filling facility. With a product such as a pandemic flu vaccine, the speed and efficiency of the filling unit operation are critical to meet market demand. The manufacturer's goal in evaluating single-use fill–finish was to increase production without increasing its manufacturing footprint.

The single-use assembly consisted of a filter module connected to a 50L header bag, a pump line and needle assembly. For the isolator extension, a Getinge LaCalhene alpha port was added to the current restricted access barrier to permit the sterile transfer of fill lines and needles through the connection to the mating single-use Getinge LaCalhene beta bag. The flowpath was selfcontained and had limited assembly, increasing operator safety and reducing contamination risk. The hard piped filling module was replaced by a roll-up peristaltic pump skid to add flexibility to the existing line, which can now run fixed setups with time pressure, as well as single-use assemblies through an alpha beta connection for new products.

The comparisons between the traditional and single-use fill finish processes at this manufacturer are shown in Table 2. Overall, the campaign fill time was reduced from 36 h to 12 h. In the new configuration, the rate-limiting factor in manufacturing became the preparation of the drug formulation rather than the facility.

Table 2: Comparison between a traditional and a single-use fill–finish process at a pandemic flu vaccine manufacturing facility.

The new process required less than six months to commission, and in the 85 million doses filled to date, there have been zero contaminations. Equipment utilisation increased from 35% to 82%, and there was a significant drop in energy use due to the elimination of CIP/SIP.

Conclusion

A growing number of pharmaceutical and biopharmaceutical companies are exploring the potential of single-use systems to deliver lean process improvements. The main drivers for adoption are rapid facility start-up, flexible operations, and elimination of the chemical, utility and labour requirements for cleaning.

When incorporated as part of a larger, overall strategy to reduce waste and process time, improve process consistency and facilitate technology transfer, single-use systems can deliver measureable benefits and impact the bottom line.

Vikas Gupta is Merck Millipore Group Product Manager, Mobius Single-use Products and Services. vikas.gupta@merckgroup.com Tel. +1 781 533 3264

References

M. Holweg, Journal of Operations Management 25(2), 420–437 (2007).