	Advanced biopharmaceutical manufacturing technologies, including continuous biopharmaceutical manufacturing, are among the "emerging priority" areas highlighted in an April 2016 report, “Advanced Manufacturing: A Snapshot of Priority Technology Areas Across the Federal Government,” by the Subcommittee for Advanced Manufacturing of the National Science and Technology Council. The report lists a range of advanced manufacturing technologies that the US government believes will improve the economy and create jobs. Federal funding is already going into research and development of these areas, with many projects ongoing. 

	"A vibrant manufacturing sector, especially one invigorated with the latest technologies, requires focused investments along the entire technology innovation pipeline," wrote Tom Kalil, deputy director for Technology and Innovation Office of Science and Technology Policy, in the report. "An innovation pipeline stocked with ideas, from the laboratory bench to the manufacturing shop floor, is required to 'make it here' so that we can 'sell it everywhere.' The advanced manufacturing processes and products we desire-the types that lead to greater economic prosperity-is the result of knowledge, accumulated through research and development, translated systematically into know-how.”


	One of the emerging priority areas is engineering biology-designing and tailoring biological systems to manufacture products. This field evolved from bioprocessing expertise in the US, says the report. Engineered cells produce proteins for biopharmaceuticals, as well as fuels, chemicals, and biomaterials. Designing reproducible, robust, and stable processes in a bioreactor is a challenge that will require multiple approaches. The report notes, "These approaches include a clearer understanding of the biological mechanisms underlying DNA stability and repair, epigenetics, and evolution, as well as development of quantitative tools that enable the prediction of complex biological designs in a manufacturing environment.”


	A second emerging priority area related to biologics is regenerative medicine. "Regenerative medicine, and the clinical use of stem cells, has the potential to repair or replace dysfunctional, degenerating, or absent cells, tissues, and organs. … Additionally, engineered cells can be used to redirect immune function and enable the emergence of 'immuno-oncology,'" says the report, which adds that the US government invested $2.89 billion between 2012–2014 in regenerative medicine, primarily for the development of therapeutic techniques and technologies. A focus on process engineering is crucial to achieve manufacturing reproducibility. The report describes several challenges:

“Manufacturing cell and tissue products is significantly more challenging than manufacturing biopharmaceuticals. This is because manufacturing release criteria for bioengineered cells, tissue, and organs are largely undefined; the mechanisms by which these living products produce their effects are poorly understood; and they contain active cells which continue to grow and evolve. Additional challenges for manufacturing cell-based products stem from the complexity of the product and the bioreactor process. These challenges include appropriate design of bioreactors for adherent cells; characterization of the product with measurements that predict the clinical effectiveness of the product; determining tolerances of variation in cell types; how to store, ship, and deliver product with a very short (hours-long) shelf life; and how to assess the purity of the product in minutes or hours, instead of days. Development of methods to address the long-term storage of cells as manufacturing inventory is essential to increase their flexibility, reliability, and cost-effectiveness.”


	A third area of emerging priority in the report is continuous manufacturing for both small- and large-molecule pharmaceuticals. Regarding biopharmaceutical production, rhe report notes that continuous perfusion and fermentation systems are being used, but needed improvements include "the development of robust and stable cell lines that maintain high productivity over prolonged time periods (e.g., 2–3 months), design of media formulations to support high cell density, and optimization of bioreactor conditions to provide the high cell density at high viability and positive growth rates. Various enabling technologies, such as automatic cell density control, efficient oxygenation and ventilation, and foam control, must be developed and optimized." Work is also needed in continuous downstream purification for improved scale-up and development of continuous viral inactivation and removal. According to the report, "An important design requirement for all continuous downstream unit operations is that they must operate over prolonged periods under stringent sterility control conditions, which will require novel and unconventional solutions."

	Continuous manufacturing processes require real-time analytics. In biopharmaceutical processes, process analytical technology (PAT) is needed for attributes such as activity, aggregation, glycosylation, and impurity level. PAT for biopharmaceutical processes today is often customized, which restricts widespread adoption, says the report.

	Several federal programs are involved with developing continuous biopharmaceutical technology, including NIST, Defense Advanced Research Projects Agency (DARPA), and Biomedical Advanced Research and Development Authority (BARDA). The DARPA program aims to "enable timely response to patient needs and emergent threats by developing miniaturized and distributed manufacturing platforms to produce multiple small-molecule active pharmaceutical ingredients and protein therapeutics on demand." Exploratory studies under contract to BARDA are also investigating continuous manufacturing processes. Representatives from BARDA will be speaking about medical countermeasure manufacturing as part of a 

session on reducing drug shortages at INTERPHEX on April 27, 2016

Executive Office of the President, National Science and Technology Council

Articles

Production Trends

The Subcommittee for Advanced Manufacturing of the National Science and Technology Council highlights biopharmaceutical manufacturing as an emerging priority.

US National Science and Technology Council Promotes Advanced Manufacturing

	A wide range of filling and packaging equipment, as well as packaging materials, will be displayed at INTERPHEX (April 26–28, 2016, Javits Center, New York, NY).


	CSP Activ-Blister materials from CSP Technologies protect moisture- and oxygen-sensitive solid doses packaged on thermoform-fill-seal and fill-seal equipment. Using silica gel and molecular sieve technology, outfitted blisters can absorb tailored amounts of water vapor, oxygen, or a combination of the two, and can be produced in shapes and sizes to accommodate any tablet and capsule size. (1).

	Other material innovations include several specialty packaging materials from ACG North America: anti-fog NoMist film; UniDose single-dose packaging film; thermoformable, silvery Alukbliss film; and Immaculid polyvinylidene chloride-coated paper lidstock. The company also plans to display the Quest Nanoblis machine, a tabletop blister packer for low-volume runs such as feasibility studies (2).

	For bottle packaging of solid doses, the Cremer CFS-622*4 tablet counter from NJM Packaging with Optel CountSafe vision inspection system and automatic tablet ejection handles tablets, capsules, and softgels at speeds up to 200 bottles per minute. The modular design accommodates one, two, three, or four counting modules, each with six discharge channels. Integration with Optel’s CountSafe guarantees 100% rejection of rogue doses, defects, broken product, and foreign material. The CountSafe inspection system verifies dose color, size, and shape and rejects any nonconforming objects. Because only good product is bottled, product loss and rework is minimized (3).

	Quality control needs also will be addressed by the TabletProof 360 inspection system from Optel Vision, the TCI tablet and capsule inspector from Antares Vision, an Anritsu checkweigher from MG America, and the enhanced PharmaFlex iSeries deduster from Pharma Technology.


	The monobloc design of the compact Extrafill syringe filling system from Marchesini Group positions two tub opening and syringe filling/stoppering stations under one isolator. Speeds up to 200 syringes per minute can be achieved by adding one, two, or three more stoppering stations. A robotic arm peels off the protective Tyvek lidstock and pushes the tub onto a loading belt. To prevent contamination, syringes are centered and completely protected during the sterile filling process. Peristaltic pumps control filling (4).

	Another robotic vial filling system, the Steriline RVFCM50 filling and capping machine from MG America, has an effective output of up to 50 vials per minute, and can handle vial sizes from 2 mL to 100 mL without changing format parts. Integration with an RA-V4 rotary vial washer, ST2 CCS depyrogenation tunnel, and EDM-C external decontaminating machine creates a complete line (5).   

	Designing the top plate of the filler into the isolator, and manufacturing the units simultaneously rather than sequentially, cuts capital costs and delivery time for the Dara Moduline filling system from NJM Packaging. The system handles ready-to-use vials, syringes, and/or cartridges in nests or tubs or supplied in bulk (6).  

	A vial innovation, Flexi-Cap Protect from Schreiner Medipharm, adds a base cap to the top label/cap combination of the original Flexi-Cap design. The base cap protects the bottom of bottles or vials against glass breakage and surface contamination. The label, which can be designed with a foam layer to increase protection against lateral impact, attaches both caps and completely protects the surface of the container (7).

	Contract packager Whitehouse Laboratories, which was recently acquired by Albany Molecular Research, will stress its expertise in container/closure integrity and container leak testing. “As a leading expert in the area of testing specific to 

 <1207>, attending INTERPHEX provides us an opportunity to share insights into best practices to evaluate and manage a product’s development and approval to ensure regulatory compliance for package integrity,” commented Mark Stier, general manager of Whitehouse Laboratories, in a press release (8).

		CSP Technologies, “Answers to CSP Questions,” Email, Mar. 23, 2015.	

		Reed Exhibitions, “ACG Worldwide to Exhibit Wide Range of Technologies at Interphex 2016,” Press Release, Mar. 21, 2016.	

		NJM Packaging, “NJM Packaging Introduces the Cremer CFS-622*4 Tablet Counter with Optel CountSafe Inspection and Ejection Systems,” Press Release, Feb. 9, 2016.	

		Reed Exhibitions, “Marchesini Group to Launch New Technology at Interphex 2016,” Press Release, Mar. 7, 2016.	

		MG America, “At Interphex, MG America to Introduce New Machines, Including Next-Generation Planeta Capsule Filler,” Press Release, Feb. 23, 2016.	

		NJM Packaging, “NJM Packaging Introduces Dara Moduline™ Aseptic Filling System Inside an Isolator,” Press Release, Feb. 25, 2016.	

		C. Dale, “Interphex Booth Interviews,” Email, Mar. 16, 2016.	

		Whitehouse Laboratories, “Whitehouse Laboratories to Exhibit at Interphex 2016,” Press Release, Feb. 29, 2016. 

Packaging

Packaging innovations displayed at INTERPHEX include advanced materials, inspection systems, and filling systems.

Previewing Solid Dose and Parenteral Packaging Innovations at INTERPHEX

	The benefits of adopting single-use technologies in the production of biopharmaceuticals, such as lower capital investment and increased flexibility, are now well documented and widely recognized in the industry. But when building a new facility based on single-use technologies, or incorporating single-use into an existing facility, how do companies ensure they fully realize the benefits?

	Facility design is a complex, multi-faceted, multi-step process, and early decisions can cause unforeseen limitations as the project progresses or, later, when further development of the facility is required. Asking the right questions at the outset and having the depth of experience and knowledge to understand the consequences of the answers are vital to establishing the right specifications during the design phase.

	Identifying a partner or partners to support the design and build of a facility and the process that sits within it is the first key decision. Traditionally, an architectural and engineering firm and one, or possibly multiple, single-use process-equipment supply partners are selected. Working with a single external point of contact can help drive efficiencies in project-management and delivery. To be successful, however, the lead partner will need an understanding of biomanufacturing facility design, engineering, qualification, and validation, as well as the operational aspects of combining process hardware, single-use consumables, and automation platforms.

	Overall, there are four sets of requirements to consider: product(s) to be made, process technologies, facility design, and supporting services. In each case, a series of questions will help identify objectives, design specifications, and potential constraints.

 The first element that defines any biopharmaceutical manufacturing facility is the product itself. Will the facility be manufacturing monoclonal antibodies, recombinant proteins, vaccines, antibody-drug conjugates, or fragment antibodies? Also, will the products be mammalian cell-derived or microbial cell-derived? While these questions are most pertinent for the selection of the bioprocessing technologies required, they are also important for the design of the facility itself.

	The promise of flexibility and simplification are often major deciding factors for choosing single-use technology. Removing the need for cleaning and sanitization, for example, means that switching between one product and another becomes quicker and easier. One way to take advantage of this flexibility is by making the facility multi-purpose (i.e., the manufacture of two or more products) to drive greater facility utilization. Deciding between a single- or multi-product facility impacts facility design considerations. Factors such as avoiding cross-contamination between products and ensuring that process-specific equipment can be moved around efficiently or housed nearby for rapid changeover need to be built into the design. 

 With the plethora of regulatory guidelines and associated compliance requirements to adhere to when building a facility, it must be clear whether the product is for research and development purposes (pre-clinical), clinical trials, or commercial scale, as this will define the relevant GMP requirements. Also, if producing at commercial scale, which regulatory standard is needed? Is the product approved by FDA, the European Medicines Agency (EMA), the China FDA, Brazil’s National Health Surveillance Agency (ANVISA), or other agencies? In some cases, local requirements go beyond global ones. For example, Chinese fire regulations demand a greater level of fire resistance than is typical globally, and in countries such as Korea and Japan earthquake-proofing measures may have to be implemented.

To define the necessary capacity of the facility, the primary question is how many batches per product per year are needed? However, this number has not always been defined when the facility design stage is reached. Alternatively, it should be possible to consider what quantity (in kilograms) of the bulk API needs to be produced for each product within the facility per year to meet clinical trial or commercial market requirements, and then work back to the number of batches.

	For example, one can consider 2 x 2000-L bioreactors running a typical 14-day incubation period staggered a week apart, which equates to one batch produced each week. A typical batch at 2 g/L with a 70% overall yield in downstream processing and a 95% production success rate will therefore yield 138 kg/yr in total. The final yield here is determined by the product titer of the production bioreactor, combined with the efficiency of the downstream purification steps, both of which will be driven by the details of the bioprocess itself.


	The next step is to drill down into the discrete unit operations of the biomanufacturing workflow. If the production process is already defined, it should be listed out, but if not, then the contracted partner may be able to provide an equipment list with flexible process capability. 

 shows an example of a production process from cell culture to bulk drug substance.  


	Starting with upstream, the status of the cell line and whether the process should be batch, fed-batch, or perfusion needs to be decided. Details about the nature of the process also need to be captured, including the bio-safety level and lengths of culture time for the seed and production bioreactors.

	Moving to downstream, the overall yield of the purification process from post-cell culture harvest through to purified bulk API should be provided, along with an estimate of the step yield of each unit operation. If chromatography columns are used in the process flow, also specify the column volume and diameter required along with the desired number of cycles for each step.

	Many single-use consumable supply partners now offer large customized system designs that can be tailored exactly to a specific workflow. Having an all-encompassing single-use system for a unit operation may seem to be the most efficient option. However, manufacturing a large single-use system comes with challenges. Packaging size and transportation integrity, sterility validation, component supply, handling and staging, installation, and operational use can all become more difficult and lead to greater risk levels. In some cases, defining and selecting smaller and simpler single-use systems to function in a modular workflow can be beneficial for minimizing risks.

	Another important consideration in selecting single-use consumables is ensuring the supply chain is robust. Switching out any element of a validated process requires significant additional work. Therefore, make sure the supply partner has a proven track record, a materials policy in place, transparency on how they work with raw material suppliers, and a proactive communication program, and that they can provide examples of how they have dealt with previous situations of raw material changes. Also check the robustness of the qualification and validation package supplied, and make sure it meets all relevant regulatory requirements.
	
	


	The crucial point in designing a new facility is whether it will be a brownfield/renovation or a greenfield site. If it is brownfield, then designers and engineers will need to know if the footprint is fixed and whether there are any restrictions on the space, such as floor strength, ceiling height, or door and elevator sizes. When thinking about the layout, are there existing personnel, product, or material flows already in place? Also, is there existing support infrastructure, such as utilities, warehousing, or laboratory space, that can be accessed? If possible, plans for future plant expansion at the site, or at other sites, should be taken into account, particularly if they will have an impact on the product requirements of the facility being built now.

	If it is a greenfield site, then there is increased flexibility in what can be built. However, sourcing an engineering firm with the relevant experience for a stick-built biopharmaceutical facility design can be challenging in some parts of the world. In response to this, another option that has emerged is the modular facility, made from standardized prebuilt units delivered to the greenfield site. This approach can have benefits in ensuring consistent standards of quality and reduction of time to first batch. This modular approach to building allows site excavation to run in parallel with module construction and validation of unit operations to begin offsite.

	For those on a brownfield site or those building a new facility adjacent to an existing one, any current centralized automation platform for data archiving and process monitoring may need to be linked to the new facility. In other cases, a standalone automation platform will be appropriate.

	Finally, the need for any additional support functions or buildings should be decided (e.g., fill and finish building, a black utility generation building, a warehouse, quality control [QC] laboratories, or a waste treatment plant).

	The needs here can sometimes run counter to expectations. For example, when embarking on a first foray into single-use, many presume that the removal of the hard piping and utilities needed for clean in place of stainless steel will result in a reduced footprint requirement. What is not always anticipated is the warehousing requirements for the stock of single-use consumables, which also need to be unpacked and prepared in a staging area. While having adjacent warehousing on a site may fulfill this need, more efficient tracking, set-up, and speed of changeover will be achieved if some consumables staging and storage sits within the facility itself, in close proximity to, or as part of the cleanroom environment. In total, the footprint is likely to be reduced in switching from stainless steel to single-use, but the change is not always as significant as expected.

	When adding a single-use train to complement existing stainless-steel production facilities, the flexibility of single-use can help reduce the need for additional utilities. In one case, when designers and engineers looked at which existing underutilized utilities could be shared with a new single-use set-up, it turned out to be a significant amount. For example, the flexibility of single-use meant that single-use unit operations requiring a water supply could be scheduled for the downtime or periods of low water consumption of the stainless-steel process. The reduced consumption of utilities required to operate the single-use process allowed for easier integration of additional capacity into the existing infrastructure of a production site.


	The ability of operators to safely work with biologic and potentially hazardous materials at any stage during the process is a key facility design consideration. Knowing where to place biosafety cabinets, if aseptic connections are required, and knowing any special design modifications to the single-use system (e.g., extra clamps, material selection, handling of highly toxic excipients) is vital.

	Next, if known, specify the buffer and media requirements of each unit operation step in the production process, including whether any solutions require special handling (e.g., 70% ethanol), if steps are time-constrained (e.g., a highly-labile product that must be processed in a specified period), or if temperatures other than room temperature are required (e.g., temperature-sensitive media for upstream or cold purification processing).

	The buffer preparation schedule for downstream purification can have a significant impact on facility design. Whether it is just-in-time preparation, one day in advance of use, or before any purification is started, will influence how much space is required for buffer storage or whether a system of built-in piping is required.


	Facility design is a multifaceted, interlocking web of needs, wants, and risks, and it must be properly managed from the outset to accommodate and account for all requests. Management includes being able to step back and take a holistic view. The prime driver and desired outcome, whether it is shortest time to market, lowest overall cost, or capital preservation, will significantly direct the decisions made at all stages of the design and building process.

	For example, for a small biotech that was particularly concerned about reducing capital expenditure, the ultimate recommendation was to buy-in ready-made buffer and media in single-use liquid delivery bags. The overall scale and output of the facility was relatively low, and therefore the additional infrastructure required for in-house preparation was not going to drive significant savings in the longer term. This change in processing methodology minimized both footprint and utility needs.

	Another element to consider at this point is how much “future flexibility” to account for during the design and build phase. Do you want to allow for the possibility of adding more production bioreactors to expand manufacturing capacity? Do you want to add 10% more communication drops for the integration of future equipment? The balance to be struck is between too much and not enough.

	One reason such flexibility is important is that future manufacturing needs are always uncertain. Factors such as increased productivity and titer, coupled with increased market competition due to products coming off patent, has led to some stainless-steel facilities becoming underutilized and ending up shut down or sold.
	The facility itself is only the beginning. Operational training will be required, as a minimum, but many supply partners can offer a much wider range of services. Validation requires significant experience and know-how and has the potential to consume significant internal resources. Outsourcing this element to an experienced partner can be a cost-effective option.
	Ultimately, of course, budget is a crucial factor, along with when production needs to commence. But these should be considered alongside a close appraisal of the experience and depth of knowledge of the team that will be delivering the project. By mapping skills against requirements, it is possible to identify key attributes external partners need to have to make a project a success, first time.


	Peter Genest is global operations manager, FlexFactory, tel: 1.860.670.3014, pete.genest@ge.com, and John Joseph is engineering project leader, both at GE Healthcare’s Life Sciences business.

:
	When referring to this article, please cite it as P. Genest and J. Joseph, "Designing a Biomanufacturing Facility Incorporating Single-Use Technologies," 

Troubleshooting

Asking the right questions is crucial to establishing a biopharmaceutical facility design.

Equipment and Processing Report-04-20-2016

US National Science and Technology Council Promotes Advanced Manufacturing

Previewing Solid Dose and Parenteral Packaging Innovations at INTERPHEX

Designing a Biomanufacturing Facility Incorporating Single-Use Technologies