New Directions in Modular Manufacturing

Pharmaceutical manufacturers have begun to invest more heavily in modular manufacturing equipment. Modular equipment is attractive to pharmaceutical companies because it adds portability, ease of scale-up, and flexibility to facilities. As modular manufacturing becomes more popular, however, companies may face regulatory challenges, particularly when entering emerging markets. In this article, Sue Walker, Provantage E2E Solutions, MilliporeSigma; Helene Pora, PhD, vice-president, Single-Use Technology, Pall Life Sciences; and Parrish Galliher, chief technology officer, Upstream BioProcess, GE Healthcare Life Sciences, give an overview of recent trends in modular manufacturing and common challenges manufacturers face when implementing modular systems.

Recent advancements

PharmTech: What are some recent advancements in modular bioprocessing technology?

Galliher (GE Healthcare): Biopharmaceutical companies are under constant pressure to reduce both time to market and costs. The advent of single-use technologies has simplified facilities, resulting in a resurgence in interest in modular facilities. Taking a modular approach can significantly reduce time to install GMP manufacturing capacity, allowing capital investment costs to be deferred until the drug is further into clinical trials and the chance of success is higher.

Prefabricated modular facilities enable a parallel construction methodology that reduces start-up time through a standardized and optimized design involving prefabricated modules that are manufactured in a controlled environment and shipped to the site of choice. At the same time, the site is prepared and the single-use processing equipment is produced. There is also the opportunity to develop an agile, single-use based manufacturing process that can be further optimized to facilitate multi-batch processing and smaller batch sizes. To facilitate this optimization, single-use equipment is placed on casters to be movable in the facility so that the process equipment trains can be configured or reconfigured based on processing plans in a matter of minutes.

This parallel process dramatically reduces the construction and commissioning of the manufacturing facility and ensures that a company can duplicate these facilities anywhere in the world. More companies are realizing that they can refocus their engineering efforts into looking at complete solutions from suppliers who have expertise in both facility construction and the bioprocessing technologies inside.

Pora (Pall Life Sciences): The trendiest modular bioprocessing option today is the factory in a box. This model looks to deliver all the elements of a bioprocessing facility in a portable format that is easy to set up and use; limited resources, such as water, are needed to operate them. This trend has two key drivers:

• Localization: Manufacturers are seeking more versatile options, especially when the technology is being placed in an area that lacks basic infrastructure.

• Time to market: Particularly in emerging markets, time to production is key. So in addition to looking for something that is quick to set up and operate, there is also the need for reliability; and safety is also critical.

Walker (MilliporeSigma): Recent trends that are key drivers for modular bioprocessing technology include:

• Upstream processing titer increases of 2X to 5X and downstream processing purification yield improvements. These improvements lead the way for smaller-scale processes in multi-product facilities with closed processing options.

• Greater process flexibility for better facility utilization with a focus on continuous manufacturing.

• The ability to template or clone processes and repurpose facilities.

• Overall reduction in the cost of goods (COGS) through productivity enhancements.

PharmTech: How has modular biomanufacturing equipment changed the design and operations of biopharmaceutical facilities?

Walker (MilliporeSigma): The process, and therefore the equipment that makes the process a reality, is still the focus for any facility design. But now the equipment does not have to be stationary, it can be mobile. Equipment mobility will have a direct impact on all door and hallway dimensions. A central corridor design may be required for ease of transport.

The ability to move equipment in and out of the production suite and to quickly and easily prepare for the next run will increase the available time for production. Gamma irradiated (pre-sterilized) assemblies and in-process aseptic connection/disconnection technology have made this possible, along with the potential for a closed process. But the ability to store one process intermediate while simultaneously starting a new process may require data to extend existing hold times or additional stability studies.

Process flexibility, reduced capital expenditure (CAPEX), shortened timelines to facility start-up, and rapid suite configuration and changeover are some of the changes realized with modular biomanufacturing equipment.

Galliher (GE Healthcare): Modular single-use facilities offer rapid and minimally disruptive plug-and-play reconfigurability and expansion ease. In addition, facilities that are designed for single-use processes typically have a smaller footprint since equipment required for clean in place (CIP)/steam in place (SIP) such as steam generation and distribution is eliminated. A smaller footprint can equate to lower initial costs to build, and lower ongoing operational costs.

A single-use facility generally has a flexible design that provides agility for future product needs and capacity changes. Extra undefined expansion space is often designed into these facilities at the beginning so that scale-out expansions can be implemented quickly down the line.

Pora (Pall Life Sciences): Modular biomanufacturing facilities support the concept that a manufacturer can create a totally single-use bioprocessing facility that is just as effective as a legacy facility. The difference is that this type of facility is easier to install and delivers drastic reductions in the resources traditionally needed to operate a biomanufacturing facility (water, footprint, operator, etc.), while still offering strong output.

Equipment challenges

PharmTech: What are the pros and cons of incorporating modular equipment into legacy conventional biomanufacturing facilities for hybrid operations?

Pora (Pall Life Sciences): There is a wide range of size options across legacy and modular technologies, so the real question is how much of a facility already exists. If a manufacturer has a traditional facility, they will be looking at the integration of individual technologies, because it is advantageous to optimize existing resources rather than having to start a facility all over again. The greatest opportunities are in the green fields, such as emerging markets that lack existing infrastructure, or for companies that are starting a production facility from scratch.

Walker (MilliporeSigma): The advantages can include:

• The ability to directly scale the bioreactor used for mammalian cell culture from 3L to 200L to 2000L

• Pre-assembled, gamma-irradiated process flow paths

• Connectors that allow for aseptic connection, disconnection, and reconnection while containing process fluids

• The base unit contains the support structure and any common hardware necessary for operation of a core unit. The core unit contains the hardware/equipment that is specific to a given unit operation, such as chromatography. Once processing is complete for a given unit operation, the core unit only would be exchanged for a second unit operation, such as tangential flow filtration, and vice versa. This will result in a reduction in CAPEX, space required in the GMP area, and operator training.

• Overall savings through elimination of CIP)/SIP and associated chemical, energy, and time requirements

• The use of a process template (or process platform) that has been developed and optimized from experience with a similar type of molecule.

• Operator ease of use.

The disadvantages can include:

• Different logistics and warehouse requirements

• Scale limitations with bioreactors up to 2000L and other general handling/storage up to 3000L.

Galliher (GE Healthcare): Manufacturing process designs for modification of existing facilities are often a hybrid of legacy components and unit operations that must be integrated for optimum efficiency. Modular or single-use platforms reduce the need for CIP and SIP and therefore offer increased flexibility, reduced contamination risk, less disruption, and faster installation and turnaround times between batches. However, single-use bioreactors are limited to 2000---3000L capacity, which, even accounting for the higher titers that can now be achieved, will still not be suitable for multi-ton facilities. When incorporating single-use products into existing processes, companies should be prepared for the fact that utilities and communications infrastructure may need to be further optimized to ensure a seamless and integrated hybrid process.

Regulatory challenges

PharmTech: What are some regulatory approval challenges?

Walker (MilliporeSigma): The two key areas of focus from a regulatory perspective are vendor qualification for supply chain control and extractables/leachables assessment of the single-use assemblies. These areas can be successfully addressed through partnership with a qualified vendor that is responsive to both client and industry needs.

Pora (Pall Life Sciences): The regulators are no longer differentiating between legacy or modular technologies, so the regulatory challenges remain the same: proving safety, efficacy, and reproducibility of product with the technologies being used.

PharmTech: What are some of the sourcing barriers for single-use equipment needed for modular manufacturing units?

Pora (Pall Life Sciences): Integration and standardization remain the greatest barriers across the single-use spectrum. The question is, how are people looking to buy these technologies, and who is selling all the required components to bring them to life? Considering that there are usually multiple suppliers, users really need to identify how they will handle the supply chain if bits and pieces of the system are arriving at different times; this becomes even more critical in a pandemic.

Galliher (GE Healthcare): The demand for single-use systems continues to rapidly increase. This has led to increased delivery times compared with just a few years ago, something suppliers are internally addressing so that they are able to meet market demand more efficiently.

Delivery can be more difficult for single-use facilities in developing countries that rely on overseas supply chains to provide consumables to local facilities. This overseas sourcing can slow down delivery.

Walker (MilliporeSigma): One sourcing barrier for single-use equipment is the lead time. While typical lead times for single-use equipment will be shorter than stainless-steel equipment because there is more standardization in the designs, they will still need to be accounted for in the overall project planning. There may also be a concern over having a single source for the process assemblies that can be addressed through supply agreements.

Facilitating scale-up

PharmTech: How can modular manufacturing equipment facilitate scale-up steps?

Walker (MilliporeSigma): In general, the equipment has been designed to accommodate a templated process at selected batch sizes for direct scalability. The upstream process is a good example. High-throughput screening can be accomplished very efficiently using spin tubes. Once the top media and feed candidates are selected, they are tested in a 3L single-use bioreactor format. The data obtained in the 3L bioreactor are directly scalable to the performance in the 200L and then the 2000L single-use bioreactor. The process is extremely efficient at screening candidates while at the same time allowing predictability at production scale.

Galliher (GE Healthcare): Instead of scaling up, single-use facilities are usually designed to scale-out by adding more lines of the same scale as production requirements increase. Some single-use downstream steps have reached their maximum capacity at the moment and further development will be needed to add additional capacity. This is often solved by adding a second skid/module or scaling out at that particular step.

Pora (Pall Life Sciences): Whatever solution is chosen, the goal is to shorten commercial manufacturing timelines. A manufacturer will need to consider how their equipment choices will affect versatility as they look to scale-up a bioprocess. It is important to note that modular technologies can often facilitate more rapid scale-up due to their intensive use of single-use technologies.

Portability considerations

PharmTech: Please discuss the portability of modular manufacturing equipment. How might these portable systems aid in emergency situations?

Pora (Pall Life Sciences): This is where the conversation gets tricky because while these systems are more portable, they still need to be shipped in a way that is safe and effective. The boxes have to be big enough, and all the components need to be accounted for. Their portability is particularly useful in case of emergencies, but the customer needs to know that the equipment can get there quickly and will arrive ready to go. It is a complex process, and one that the industry is still ironing out.

Walker (MilliporeSigma): Modular biomanufacturing equipment has been designed to be mobile and to accommodate smaller scales of operation. In addition, the added benefits of process flexibility, reduced CAPEX, shortened timelines to facility start-up, rapid suite configuration, and changeover can make them well suited for emergency or epidemic situations. In general, for any emergency situation, the key is understanding the process and having an equipment template that meets the process needs. The equipment would then be available and in the case of a modular facility, validated, and ready to go.

Galliher (GE Healthcare): Modular single-use equipment is easily portable since minimal utility connections and services are required. In the event of a pandemic outbreak or emergency situation, these facilities could be put on trucks and transported to the locale of the emergency.

PharmTech: How feasible are portable systems in the event of an epidemic?

Walker (MilliporeSigma): The question of epidemic preparedness needs to start with an investment in vaccine research and the development of new tools and approaches or in adapting the existing drug and vaccine platforms for more general applicability. Adaptable platforms could allow for rapid response in a crisis situation. In addition, this may require a global epidemic drug approval process or at least a clear regulatory pathway to allow for the use of the platform process under accelerated timelines. The development of adaptable process platforms and their pre-approved regulatory status could then allow the facility to be predesigned, validated, and ready-to-go during a time of crisis.

Pora (Pall Life Sciences): Realistically, they would be more feasible in a pandemic, and while it is doable, the manufacturer has to think about the full module. They need to know what the architecture is, and how it operates. The goal here is to be prepared and to have already worked with the module so that in the case a pandemic happens, there are no surprises and the customer can just press a button to bring more capacity online. However, there are external elements affecting the feasibility of this approach, such as the local workforce and whether they are trained and ready to set up and operate the portable biomanufacturing facilities.

PharmTech: What are the specific in-country barriers that exist to setting up portable manufacturing units?

Pora (Pall Life Sciences): There are two main issues, particularly in emerging markets:

• Regulatory requirements: Is the user clear about the requirements to be met; is further information required?

• Knowledge transfer/workforce: Again, are the human resources available to effectively set up and operate a modular facility as needed?

Walker (MilliporeSigma): While not necessarily a barrier, all local regulatory requirements must always be successfully met. In addition, there may be local laws that prohibit or that make it difficult to employ portable manufacturing units. These will need to be assessed on a case-by-case basis. It is important to have a partner that is familiar with handling facility construction and pharmaceutical production on a local scale.

Galliher (GE Healthcare): Some countries such as China, Brazil, and Russia are emphasizing in-country, for-country manufacturing. As a consequence, many companies are building local facilities so they can gain the required approvals and market their biotherapeutics in those countries.

PharmTech: What are some contingency plans that would be necessary should a modular system go off line?

Galliher (GE Healthcare): Our recommendation is to install an emergency power generator on site and connect all critical unit operation equipment to both a normal power supply and an emergency power system. Using an emergency power generator gives you an interruption of 5-120 seconds before the generator is up and running. 
All computer systems are backed up by uninterrupted power supply that has chargeable batteries. If a customer had additional needs for uninterrupted power (e.g., stirrers), then there would be a need to install a central uninterrupted power supply on site as well.

Article Details

Pharmaceutical Technology
Vol. 40, No. 9
Pages: 62–66

Citation

When referring to this article, please cite it as C. Hroncich, " New Directions in Modular Manufacturing," Pharmaceutical Technology 40 (9) 2016.