The Power of Modular Design

Posted on October 14, 2022

Hana Selvey, Technical Writer, Pall Corporation

Summary
With the demand for biologics increasing, and the need to scale productivity, provide personalized treatments and improve development timelines increasing the challenge, manufacturers are looking for more efficient and flexible ways to provide for the demand. Traditional facilities do not have the adaptability to change with ease to accommodate new therapies, so manufacturers are turning towards a modular approach. Whether it is the facility as a whole, the cleanrooms within, or down to the unit operations linked together forming the manufacturing platform, modular design has the potential to provide a solution for the increasing pressure.

Introduction
Bioprocessing facilities, manufacturing processes and individual pieces of equipment, have traditionally been designed to often optimize the manufacture of a single product. Though producing what has been asked of them for the last 30 years, increasing demand and changing socio-economic forces have put these practices under pressure to change with growing times. Yet, can these traditional processes, in a sense, be made better, more efficient, more cost effective, and is it necessary? Can changes come without undesirable compromise? Could these adaptations be the next step in the evolving world of biotherapeutics manufacture?

The ‘traditional’ facility and future needs
Small molecule and early-generation biologics were largely developed and processed using stainless steel-based technologies with an entire facility dedicated to a single product. Traditional manufacturing facilities have been purpose-built, and within these, every vessel, valve and pipe length are intricately designed for a singular purpose. This traditional approach to manufacturing, though effective for many large-scale processes, has been challenged and largely shown to not be able to meet the needs of new modalities, the changing drug development environment, and ever-increasing demand. This evolving need has seen rigid, purpose driven designs being largely replaced by those with greater flexibility and adaptability, and the value of customization has been moderated by the simplicity and speed of standardization. At first, these seem to conflict, but both can potentially be accomplished by incorporating a ‘modular’ design that can provide a way of growing with the vastly changing world of bioprocessing.

What does modular really mean?
Essentially, a modular system is a collection of units which can be constructed into a more complex arrangement. Each unit can be adapted to the procedure itself, modifying the flow for a better, more controlled outcome. However, ‘Modular’ design is not new. The concept has been around for a long time and has been incorporated into many different fields. Traditional small molecule manufacturing, for example, saw the advent of multipurpose facilities with standardized process elements and equipment. It is essentially a modular industrial-scale chemistry set in glass and stainless steel. Being small molecule, current good manufacturing practice (cGMP) was not as critical for every operation, but it was still present. The modularization of a relatively small number of individual processing steps allowed manufacturers to rapidly configure processes for small manufacturing campaigns. The opportunity is to establish solutions that deliver the same process agility for all manufacturing processes and to achieve new levels of control, performance, scalability, and productivity while adhering to all cGMP standards.

A modern challenge
New modalities seek to achieve ever-faster development timelines and ways to reduce capital risk. In parallel, the pressure to reduce the cost of development and manufacture to help make drugs and therapies accessible to a broader segment of the global patient population, grows. Fixed, traditional facilities can be seen as slow to design and slow to build. Constructing and qualifying a traditional stick-built biopharma manufacturing facility can take 3 to 5 years on average¹ and is at risk of being redundant should the product they are designed to manufacture fail to overcome the efficacy, safety and regulatory hurdles on the way to market. If, however, a drug does gain approval, the facility may find it does not have the capacity for the demand due to the inflexibility of their bespoke systems being unable to produce product to scale. If the demand for product is lower than anticipated, lower return on the investment from underutilization could occur.
New modalities also seek to improve timelines to fully take advantage of the market opportunities and to treat a population who may often have no alternative. Ways to robustly and speedily design and deliver a process allow for a delay in facility and process construction to a time when clinical data provides a better indication of subsequent clinical trial success and regulatory approval. This reduces the risk of loss in investment from redundant capital. The project schedule in a traditional stick-built facility, containing a purpose-built process, can be long and there are many factors that can lead to potential delays. These can occur at any phase in the project, from the facility and process design, to construction, commissioning, through to the process qualification. The delays can lead to financial implications or drug shortages.
So, it should be no surprise that, as well as opportunities for process intensification, ways to increase the speed of process development and design are beneficial. Some of the methods used to achieve this do not mean re-inventing proverbial wheels, in fact many of the concepts have long been established. Others, such as the implementation of single-use manufacturing philosophy, have grown in maturity to the point where they are now the dominant choice for most new biotech processes. Single-use lends its hand to making the modular systems more agile compared to the rigid stainless-steel structures in traditional facilities. This also increases scalable capacity.

How can a ‘modular’ system benefit the next step in the world of bioprocessing?
One key to progress is flexibility. Modular design concepts provide this while increasing speed by enabling the use of pre-established methods and designs. Predictable increases in speed then allow for deferred capital investment after knowledge from reaching critical milestones in the clinical development pathway is available. With 80% of candidates failing at Phase II and 40% failing at Phase III clinical trials², a modular system allows you to defer and/or reduce capital expenditure (CAPEX) as modular facilities using single-use technologies can be built faster.
A modular system can give you the chance to build a standardized system, as well as the chance to adapt a pre-engineered/pre-designed system to suit your needs. As there are many process platforms that do not vary greatly, the right equipment allows for a standardized process, which can be used by all companies, with the allowance of integration and change to meet individual requirements. This removes the need for bespoke, and often quite restrictive workflows, and brings in the opportunity for an easier pre-designed system built and assembled off site. These designs are essentially ready to order and can be pre-qualified, tested, proven, and supported with standard training packages and data packages to support rapid implementation.
Modular systems can be set up in local regions, close to where the therapies are needed, allowing for these to be delivered direct to patients in good time. Flexible biomanufacturing facilities cut out the delay of waiting on a busy CMO (contract manufacturing organization) schedule and the time taken to transport products to the location needed, allowing broader access to life saving products. A prime example of this is the decentralized manufacturing strategy illustrated by some of the COVID-19 vaccine productions.
The flexibility which comes with a ‘modular’ concept, allows for each and every unit to be slotted into place, to complete the flow path and create an efficient and adaptable system from beginning to end; either within an existing facility or a completely new one. Each unit is considered individually and constructed off site in a controlled environment. Then it is brought into the facility and installed. By following this process, it allows the project to be executed more efficiently and faster. It achieves a more predictable build, with better insight into timelines, thus reducing delays. As the bioprocessing equipment is built off-site, the installation time at the facility is shorter, again allowing for the delay in capital investment.
Moving from a bespoke system philosophy to a modular approach provides flexibility and enables the potential manufacture of multiple products from a single set of equipment. When existing production is no longer required, a modular system can be re-purposed to support the development or manufacture of another product. This removes waste, cost, and capital risk.

How can the modular concept be integrated into biomanufacturing?
Having a modular system in place does not just take into consideration the actual units within the process flow path, it accommodates the complete facility, the internal and external construction, the workforce, and the utilities. This standardized approach reduces design phases by around 12 weeks using a pre-configured design.¹
The ability to construct sections in parallel will reduce timelines to completion, which is progress compared to a stick-built facility which builds each part sequentially because of on-site restrictions. Due to strict quality control, the equipment and different sections of a modular design are built under stringent quality control parameters. This provides the documentation for regulation, making this process a more efficient one. Suppliers often provide a validation package containing standardized protocols. This reduces the need for the end user to carry out these procedures, as well as removes the need for comparability studies, speeding up the process.
The modular concept also takes into consideration external factors which could cause a build delay such as weather or labor issues. Off-site builds can remove these types of delays as the units are constructed in a controlled environment, with trained professionals under strict timelines. This removes the delays in scheduling, supply, and unexpected extra costs. Almost 80% of the build can be fabricated off-site, also decreasing project management on-site.¹
With the increased need to expand capacity, a standardized modular system removes the need to start a build from the beginning, and instead provides a fully functioning working system to order. Protocols, procedures, and training come in place with a standard design. This reduces time and cost, particularly benefiting some of the smaller start-up companies with limited funding.
A modular approach presents areas of opportunity and innovation to develop a more standardized, adaptable system to produce biologics more efficiently. It opens up a future of standardization across companies so that systems can link. It can save money long term, and provide treatment for single patients, which could not be accomplished with traditional stick-built facilities.

So, is a modular system always all-singing and all-dancing?
Yes and no. Modular concepts do come with a slightly higher upfront cost of approximately 5-10% when compared to a traditional stainless steel bioprocess train. However, this soon balances out with savings by accelerating times to milestones and utilizing the market opportunities.¹
Resistance to change is always at the forefront of development. Regulatory agencies, of course, have a responsibility to patient safety, so stringent reviewing of new technologies can often be a barrier for change.
Creating new validation protocols, and qualifying new products come with the burden of planning, documentation, and testing. Suppliers that develop systems with this in mind can provide qualification and validation packages, and critical data that eases the introduction of systems and can reduce the burden of testing. Where this is not available, added time for this step must be taken into consideration with planning and implementation.

What types of modular facilities and systems are available for bioprocessing?
Modular approaches can be observed in many areas, with layers of modularity at different scales being applied based on what technologies are available. At the facility level, a box in a box design can be provided, which is essentially a modular cleanroom installed into a shell building containing the relevant services. With this, individual units lock together and can be constructed in a matter of weeks. This provides a cost-effective solution that minimizes on site modifications, dust and possible contamination.

An example of this type of modular construction is the KUBio♦ modular biomanufacturing environment from Cytiva. When coupled with the bioprocessing solutions such as Cytiva’s FlexFactory♦ single-use bioprocessing platform, it reduces project timelines and time to market, supported by the benefits of single-use technology. With this, companies can wait until phase 3 clinical trials are complete, when the success rate is more assured, before committing capital to the build process.³
Similarly, Pall provides a range of modular platform manufacturing solutions with automated technology. The systems are highly configurable to specific requirements, with data collection all-in-one place. Examples of these include the Allegro™ Connect Bulk Fill System⁴ which is designed to accurately aliquot bulk drug substance within a closed system, saving valuable product with product recovery solutions. And the Allegro Connect Buffer Management System⁵ which provides buffer on demand, reducing the overall footprint and operator labor.

What does the future hold?
Adopting layers of modularity, including facility level, process level and system level solutions will help create an industry which provides greater certainty, speed, and quality. It allows the transformation of traditional design and construction to a more flexible and less rigid approach. Modular is not just about getting from A to B, it also provides the chance to scale up, scale down or scale out. It can integrate, it can standardize procedures and it can provide flexibility, individuality, versatility, and control. When done well, it supports process intensification and helps manufacturers develop and adapt processes in a shorter time frame.
For process flows, it is about facilitating links between the elements of the manufacturing platform and utilizing the maximum functionality of each element to gain the best possible outcome with the minimum of waste. Modularity is about looking at parts of the workflow and understanding that each step is just as important as the next, knowing that the intensification of upstream or downstream operations can only be fully realized if steps like buffer management and bulk filling are designed to make the whole process more effective, more streamlined, and more controlled. Stringent planning and design of both facility and platform, using all the tools and products at hand, can build in flexibility and scalability. Supported by the use of single-use consumables, this flexibility enables the ability to interchange products and connect and link systems results as needed to create a more efficient, economic and productive operation.
With the world seeing a higher demand for personalized medicine, flexibility is needed more than ever, and a modular system provides the flexibility with volume, enabling the manufacture of bespoke medicines for smaller populations and to quickly adapt as demand changes. Modular systems allow processes to scale up to larger volumes to meet changing demands while always maintaining the quality standards.
However, more can be done. Especially as traditional technologies are not going away just yet due to the need for larger volumes of some products⁶. More can be introduced to provide a fully closed, fully functioning automated, and standardized system to meet changing bioprocessing needs. Collaboration within the industry will increasingly allow plug-and-play automation between different technologies and make process validation faster and more efficient.
Each individual unit in a bioprocessing train can evolve further too by adopting characteristics that support modularity. Processes that have historically overcome the need for flexibility through manual processing or partial manual processing will be better supported with equipment that bakes in flexibility into the design. These will also provide full automation, total process control and automated reporting for each operation, and the supportive functions that are directly linked to that operation, and work seamlessly together.
When modularity, automation and platforms align, realizing processes that reliably deliver quality products becomes easier, faster, and more accessible to those that discover and develop life changing therapies.
This is the power of modular design.

References
1. Simpson C., Wiseman D. Improving the Biomanufacturing Facility Lifecycle using Standardized, Modular Design and Construction Approach, BioPhorum Operations Group Ltd. 2019: 7, 12, 13 Standard-Facility-Design_Biophorum.pdf
2. Norris M. Modular Processing: Enabling the Future of Biomanufacturing. 2019 Modular Processing: Enabling the Future of Biomanufacturing (pall.co.uk)
3. Cytiva Life Sciences: KUBio | Cytiva (cytivalifesciences.com)
4. Allegro Connect Bulk Fill System. Pall Corporation. 2022: 8 Allegro™ Connect Bulk Fill System – Fluid Control (pall.com).
5. Allegro Connect Buffer Management System. Pall Corporation. 2020: 1 allegro-connect-buffer-management-system-bro-en (6).pdf
6. Philips M., The Next Chapter in Single Use, The Medicine Maker, 2018: 3 single-use-the-next-chapter-art-en.pdf

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