Getting Flexible with Manufacturing

The use of flexible and/or modular manufacturing is being driven by a combination of the pharmaceutical industry’s desire to reduce costs, increase capacity, and reduce development time. Olivier Loeillot, general manager, Asia, BioProcess, GE Healthcare’s Life Sciences business; Par Almhem, president of ModWave; and Tom Ransohoff, vice-president and principal consultant, BioProcess Technology Consultants (BPTC), spoke with Pharmaceutical Technology about the latest trends in flexible manufacturing.

Flexible trendsPharmTech: What trends is the industry seeing in regards to modular and/or flexible manufacturing?

Loeillot (GE Healthcare): A facility’s flexibility depends on both the building itself and the process equipment that sits inside. We are seeing very strong interest from both Big Pharma and small, local biotechs for modular solutions, especially in emerging markets. Disposable equipment is also becoming the solution of choice for most companies wanting to maximize their flexibility and improve the cost of goods.

Almhem (ModWave): There are several trends that point us in the direction of modular and flexible solutions. These include, but are not limited to,:

• Need for new capacity driven by the risk of drug shortages as well as new product approvals

• Needs for rapid deployment in many parts of the world, including but not exclusively, as response to pandemic threats

• An increasing number of products and formulations to be produced, pushing the need for flexibility

• The increasing interest in and focus on continuous manufacturing as a way to significantly reduce process development time and manufacturing cost.

Note that modular and flexible is not the same thing. Rather, modularization is a tool to achieve flexibility, speed to market, quality, and repeatability--when implemented in an appropriate way. There are also different aspects of modularization.

A functional module has defined inputs and outputs, and a clear definition of the transformation from input to output. An example could be a mixer, with a defined input stream, clearly specified mixing performance, and defined output stream. Another example is a bioreactor with the same criteria. The definition defines the input, output, and transportation, but not the physical aspects of this module. It could also be a software module or object performing a transformation of defined inputs and outputs.

A physical module is designed to be designed, built, tested, transported, and installed as one unit. The goal here is most times off-site construction. A physical module can include more than one functional modules and could also be part of a larger functional module.

A well-executed, functional modularization allows for combining standardization with configurability and thus quality, speed, and cost efficiency with flexibility. At the same time, a well-executed, physical modularization allows for off-site manufacturing with associated speed, quality, and repeatability benefits. The keywords here are ‘well executed,’ as a thorough understanding and experience is needed to fully take advantage of the potential of modularization when designing and building for quality and flexibility.

Ransohoff (BPTC): One of the most important long-term trends in the biopharmaceutical manufacturing industry is the need to reduce the time and costs of development activities. Included in this category are the time and costs related to construction of new manufacturing capacity--either to support supply for clinical trials or commercial production. Technologies that enable more modular and/or flexible manufacturing facilities are being adopted more broadly because they enable companies to reduce time and/or costs of constructing new capacity in many situations.

PharmTech: In what areas, processes, or markets is flexible manufacturing being used commercially?

Almhem (ModWave): There is demand for and use of flexibility in most areas of pharmaceutical and biotech manufacturing. We see more single-use systems implemented for biomanufacturing, driven partly by flexibility demands. Well-known examples are bags for different types of media, single-use bioreactors, and use of plastic hoses rather than stainless-steel piping in biologics drug-product manufacturing. When we deliver isolators for containment, dispensing, etc., they are increasingly single use to allow for rapid changeover. When single use is not an option, cleaning between products is becoming more important. One way of improving cleaning efficiency is use of modular process equipment where components can be quickly switched out for offline cleaning. Contract manufacturers are often a driver for flexibility, as they have to be able to accommodate a wide range of products and processes.

Ransohoff (BPTC): The term ‘flexible manufacturing approaches’ can be applied to many practices, including from multi-product manufacturing, to the use of single-use or disposable equipment, and to novel facilities or process concepts, such as ballroom-style designs or continuous manufacturing. Certainly multi-product manufacturing is routinely practiced today for commercial production of biopharmaceuticals. Additionally, while single-use technologies are more commonly used for clinical production, they are beginning to be used for commercial production as well. Finally, as is the case with many new technologies, emerging markets with little established infrastructure appear to be adopting novel flexible manufacturing technologies and approaches more quickly than established markets where companies already have significant investments in conventional facilities.

Loeillot (GE Healthcare): Flexible manufacturing is now commonly used for monoclonal antibodies, as most of these products are based on a common platform. Many of the large vaccine-manufacturing companies are now trying to rationalize their R&D pipeline so that they will also be able to benefit from disposable technology in the near future. Amgen’s investment in Singapore is a great showcase of the most recent manufacturing trends, including a ballroom concept with mainly disposable technologies inside.

JHL’s upcoming KUBio facility in China will be setting an industry record as far as construction speed is concerned, taking less than 12 months from beginning of construction to completion of the facility.

Challenges in flexible manufacturingPharmTech: What are the challenges involved in implementing flexible manufacturing and what are the strategies for handling those challenges?

Ransohoff  (BPTC): There are a number of challenges involved in implementing any new technology. Specifically, for adoption of single-use equipment the challenges include: increased requirements for leachables and extractables testing and characterization; greater reliance on the supply chain and increased importance of vendor qualification; potentially higher operating costs; and increased warehousing and waste disposal needs, to name a few.

Loeillot (GE Healthcare): There aren’t any particular challenges when implementing flexible manufacturing. It is faster, easier, and cheaper when compared to traditional facilities. Running such a facility often requires training, as many operators may not yet be familiar with handling disposables. The biggest challenge may be regulatory, as some local agenices are not fully familiar with disposables. However, this is becoming less of an issue due to the increasing number of such facilities around the globe, as well as the number of Phase III products being produced in such facilities.

Almhem (ModWave): Cost tends to always be one of the challenges. Designing for flexibility doesn’t have to involve higher cost of a facility, but it often does.  It is a good idea to include a cost-benefit analysis for different aspects of flexibility during the conceptual design phase. The same goes for the use of modular solutions--these have traditionally been perceived as being more expensive to implement than conventional execution, but there is an increasing awareness that modularization can offer the same or better cost effectiveness if it is executed and assessed correctly.

Regulatory concernsPharmTech: What regulatory issues must be taken into consideration when switching to flexible manufacturing or modular facilities?

Loeillot (GE Healthcare): The key factor is to monitor extractables and leachables risks well. A disposables supplier must be in a position to confirm that its single-use product does not generate any of these risks and offer the right services to provide suitable evidence for specific customer processes.

Ransohoff (BPTC): Manufacturers must comply with the same regulations, whether they are manufacturing product in conventional or modular/flexible facilities. In either case, it is advisable for manufacturers to apply a quality-by-design approach, using appropriate risk-based assessments in developing and validating their processes and methods, consistent with current regulatory guidance.

Article DetailsPharmaceutical Technology
Vol. 39, No. 9
Pages: 52–53, 70

Citation: When referring to this article, please cite it as S. Haigney, “Getting Flexible with Manufacturing,” Pharmaceutical Technology39 (9) 2015.