	The implementation of single-use systems (SUS) for biopharmaceutical manufacturing as an alternative to or in combination with traditional stainless-steel equipment offers advantages such as reduced capital cost, faster facility construction, and more flexible and efficient manufacturing (1). In a fully disposable or hybrid facility, however, because pieces of equipment (e.g., reactors, transfer tubing, holding vessels) are now consumables, the supply to the manufacturing facility is more complex. The demand for customized systems and the overall growth of demand for SUS add to the pressure to improve supply.

	Most SUS are currently made in the United States and the European Union, but suppliers are exploring manufacturing of SUS components in Asia to serve the region’s growing biopharma market more efficiently. In September 2018, MilliporeSigma announced its first Mobius single-use manufacturing facility in Wuxi, China would begin production in 2019 (2), and in November 2018, GE Healthcare announced a collaboration with Chinese healthcare technology supplier Wego Pharmaceutical to produce single-use consumables in Weihai, China using GE’s Fortem platform film (3). Shorter lead times are one potential benefit. Local production could also reduce the environmental impact of shipping components over long distances (4).

spoke with Andrew Bulpin, head of Process Solutions at MilliporeSigma; Jeff Carter, strategic project leader at GE Healthcare Life Sciences; Eric Isberg, director of Life Sciences at Entegris; and Helene Pora, vice-president of Technical Communication and Regulatory Strategy at Pall about some of the issues facing the industry as companies look to SUS for biopharmaceutical manufacturing.

 What are some of the challenges with supplying single-use systems and components globally today?

Single-use supply chains are complex and dynamic. The large number of raw materials makes forecasting demand more difficult and requires robust materials management, supplier quality management, quality control, and business continuity planning to ensure continuity of supply. Common materials (e.g., silicone) are used across many vendors, which can create single points of failure within the supply chain for both the single-use supplier, as well as the end-users of their products.

	The key is to adopt a comprehensive, ‘risk-smart’ approach to supply continuity and control. It is important that suppliers proactively identify the potential risks and minimize the probability and impact of supply disruptions through effective demand planning/forecasting, capacity planning, business continuity planning, change control management, disaster recovery planning, supply-chain mapping, and continuous improvement. At MilliporeSigma, a cross-functional team of subject matter experts assess risks related to demand volatility/forecast accuracy, manufacturing capacity, process and equipment, sole/single-sourced raw materials, facilities (e.g., water, utilities, power, information technology/systems), and more. Risks above a certain risk priority number are mitigated and monitored. Business continuity plans are revisited on a regular basis, and risk mitigation activities are updated continually.

 One area of concern is availability of customization. Large suppliers tend to focus on systems with larger quantity production, leaving short-run, highly custom systems to small boutique suppliers. Consolidation of the single-use suppliers has exacerbated this issue.

 Sourcing and lead times have long been challenges for both suppliers and consumers, with some of the key pain points including lead times and an ever-changing and advancing industry. 

	One of the most critical challenges is that biopharma is a high-risk industry. Although there have been a multitude of advances in the industry, the fact remains that the end products being made with SUS consumables are being used in humans and can mean life or death for a patient or a patient population. Even at the clinical trial manufacturing phase, a full understanding of how the process will scale is needed. Particularly in cases where high customization can be called for, the supply chain becomes more complicated and impacts the lead time.

	Another challenge is just-in-time (JIT) delivery and customization. Warehousing requirements for larger spaces helps to solve storage and availability issues for off-the-shelf consumables but does not address the JIT approach or customized needs many consumers require for their process consumables. 

	A third challenge is that as suppliers (and the industry) evolve, product ratings, design, or supply chain sources may change, and it is critical to keep users informed. Transparency is a necessity, yet changes can impact existing processes and lead times. 

	As an industry, and through supplier associations like BPSA [Bio-Process Systems Alliance] and BPOG [BioPhorum Operations Group], we are working to overcome these challenges. There is a greater focus than ever on creating realistic supply-chain mapping models that address the global nature of today’s market. And a deeper importance is being placed on forecasting by end users so that the supplier and consumer can work together more effectively.

 Issues include logistics (including time to clear customs as goods move across borders, which can counter the speed element of the single-use value proposition) and managing complaints or investigations on product that is overseas. Geographical distances and language barriers can make general communication and relationship building challenging.

What are the challenges/potential benefits of manufacturing SUS locally in Asia?

Proximity to a large and rapidly growing customer base does allow us to step up our service level to our Chinese customers. One practical example is the efficiency of working in native language and local time zone, particularly for configured and customized single-use systems. Developing manufacturing operations in China to complement our existing single-use manufacturing network provides an added capability in how we consider and structure contingency plans to maintain business continuity even under challenging circumstances. 

	GE Healthcare published a peer-reviewed single-use system lifecycle analysis (4). The results of this analysis showed that single-use consumables provide a better choice from the environmental impact perspective vs. the clean and re-use paradigm. The more variable aspects of the single-use lifecycle analysis and some of the more environmentally impactful elements of the value chain were the distribution of what are often large volume, low bulk-density products across various distances and transportation modes. Based on this study, localized manufacturing should have a reduced environmental impact affect; of course, there are however, diminishing returns based on manufacturing facility capacity and plant efficiency. 

 With the establishment of manufacturing capacity and capabilities in China, we can reduce our product lead times and help our customers bring new products to market faster. In addition to shorter lead times, end-users can carry less inventory and have an enhanced level of supply security, with the ability to source their assemblies from multiple manufacturing sites.

	All manufacturing sites should be working under the umbrella of a single, global quality system, and customers need to qualify the new site so that they have the ability and flexibility to receive assemblies from multiple sites.

 Over the past decade, [biopharmaceutical manufacturing] has become an increasingly global industry. With SUS, the supply chain is complicated because, regardless of the location of manufacturing, the components are often coming from different areas of the globe. Although a lot of companies are considering moving production to other locations, with Asia having particular interest, questions remain. Most critically, expertise has to be there, and an often-overlooked consideration is shipping. What will the logistics look like, and how will that impact lead times? The country that any product is manufactured in will have its own resources and regulations, which will affect the ability to industrialize production. In addition to the considerations mentioned, what is really comes down to is manufacturing in locations that have the right balance between flexibility and supply. 

	2, MilliporeSigma, “MilliporeSigma to Open China’s First Mobius Single-use Manufacturing Facility in Wuxi,” Press Release, Sept. 12, 2018.

	3. GE Healthcare Life Sciences, “GE Healthcare Starts to Manufacture Single-Use Consumables in China through Collaboration with Wego,” Press Release, Nov. 7, 2018.

	4. GE Healthcare, “Single-use and Sustainability,” www.gelifesciences.com/en/us/solutions/bioprocessing/knowledge-center/single-use-and-sustainability, accessed Jan. 2, 2019.

Articles

Feature

Suppliers address complex supply chains for global biopharmaceutical manufacturing using disposable components.

Challenges for Supplying Single-Use Systems

	Demand for blister packaging will grow at a 9% compound annual growth rate from 2018 through 2022, according to a report from Technavio (1). Driving forces include low cost, patient convenience, sustainability benefits, and compatibility with anticounterfeiting, child-resistant, and senior-friendly features. According to a senior analyst at Technavio,“Blister packaging is predicted to be the most economical packaging method throughout the supply chain of a pharmaceutical product …. Additionally, blister packaging is more sustainable as it creates less landfill when compared with glass and plastic bottle manufacturing” (1).

	Unit-dose blister packaging also is recognized as a potential tool to circumvent opioid abuse. In fact, unit-dose packaging is specifically mentioned as one way to reduce the over-prescription of opioids in The Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act, which was signed into law on Oct. 24, 2018 (2). 

	In an Oct. 24, 2018 statement about the passage of the act, FDA Commissioner Scott Gottlieb, MD, noted, “The convenience of this kind of packaging could encourage prescribers to opt for shorter durations of use, thereby limiting the number of opioids dispensed to patients…. It could reduce the number of 30-day prescriptions that are still too common. Ultimately, this approach could reduce the overall number of drugs in circulation and potentially lower the rate of new opioid addiction. It could also address the problem of excess supply, leading to fewer pills left in medicine cabinets that could be inappropriately accessed by family members, including children” (3). 

	As demand for blister packaging rises, so does the range of available material and machinery options. New material choices include high-barrier materials and materials designed to create all-film blisters on strip packaging machines. The Flexible Blister from Constantia Flexibles runs on conventional strip packaging equipment and offers barrier properties and push-through opening similar to traditional thermoform-fill-seal blister packs. The Flexible Blister can accommodate various tablet sizes and shapes, as well as incorporate anticounterfeiting measures. Push-through force can be customized for child resistance or easy access. In some cases, consumer information can be attached to or printed on the Flexible Blister, eliminating the need to carry doses in a secondary paperboard carton (4). 

	Strip-packaged blisters can be produced on Siebler strip packaging equipment from Romaco Group running a patent-pending multilayer polyethylene terephthalate (PET)/polyethylene (PE)/aluminum foil/PE/Surlyn laminate or a clear barrier film from Huhtamaki. A targeted perforation of the polyester layer of the four-side-sealed pack allows press-through removal of the dose. The tear-resistant material can meet child-resistant packaging requirements. The design uses less material and costs less than cold-formed aluminum blisters. The push-through strips can be supplied in the standard rectangular format or as “design strips.” A Siebler HM 1-350 heat-sealing machine equipped with a continuous die-cutter produces special formats such as round, heart, petal, or star shapes at rates of up to 800 design strips/min (5).

	For conventional blister packs, Tekni-Films, a Tekni-Plex business, has introduced SBC 240 polyvinylidene chloride (PVDC)-coated PE film. Designed as a lower cost alternative to 4- and 6-mil polychlorotrifluoroethylene(PCTFE) or cold-formed foil, the clear, triplex material offers an ultra-high barrier to moisture and oxygen and a wider processing window than PCTFE and eliminates the need for stiffening ribs as well as the larger blister wells needed for cold forming. That means more doses can be arranged on the card or the card size can be reduced. The result is material costs savings throughout the supply chain and improved production efficiencies (6). 

	A newcomer on the machinery side, the Eagle-Omni blister machine from Maruho Hatsujyo Innovations (MHI), the US subsidiary of Maruho Co. Ltd., serves short-run production requirements (up to 20 blisters/min), as well as packaging development, prototyping, and materials testing needs. Measuring just over 2 m in length and 1.6 m tall, the compact machine offers a format area of 150 x 95 mm and a forming depth of 30 mm, with an upgrade available to 40 mm for larger dosage forms. The machine handles a wide range of forming materials (polyvinyl chloride (PVC), PVDC, PCTFE, polypropylene, PET, and foil) as well all typical lidding substrates (foil, paper, PVC, PET, and laminates) (7). 

	1. Technavio, “Blister Packaging Market in the US 2018-2022, Growth Analysis and Forecast, Technavio,” Press Release, Oct. 2, 2018. 

	2. US House of Representatives, “H.R.6 - SUPPORT for Patients and Communities Act,” 

www.congress.gov/bill/115th-congress/house-bill/6/text#toc-H496E9F6EA1E7428A8CE3BA236D8B27CA

	3. FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D., on How New Regulatory Authorities Will Assist the Agency In More Forcefully Addressing Opioid Crisis; Included as Part of the Newly Enacted Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act,” Press Release, Oct. 24, 2018. 

	4. Constantia Flexibles, “Constantia Flexibles Introduces Flexible Blister Packaging,” Press Release, Jan. 14, 2019.  

	5. Romaco Group, “Romaco Joins Industry Partners at CPhI Worldwide,” Press Release, Sept. 27, 2018. 

	6. Tekni-Films, “Tekni-Films Introduces SBC 240 Performance-Oriented Super-Barrier Coated Thermoformable Film for Pharma Blister Packs,” Press Release, Jan. 31, 2019. 

	7. Maruho Hatsujyo Innovations, “MHI Introduces Eagle-Omni Deep-draw Blister Packaging Machine,” Press Release, Jan. 10, 2019. 

As demand increases, new materials and machines broaden options for blister packaging. 

Equipment and Processing Report-02-20-2019

Challenges for Supplying Single-Use Systems

New Options for Blister Packaging