Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	Progress is being made in continuous manufacturing. A regulatory working group for continuous manufacturing from the Center for Structured Organic Particulate Systems (C-SOPS), which involved volunteers from 16 companies, submitted a best practices guide for continuous solid-dosage drug manufacturing (1) to FDA in June 2016, which was subsequently posted for public comment on June 23, 2017. The document was developed in response to an FDA invitation, and it describes methodologies for “selecting, specifying, implementing, controlling, and optimizing” continuous systems for oral solid-dosage drug manufacturing (1). The document explains fundamental engineering concepts, describes key differences between batch and continuous systems, and reviews process monitoring and control and sampling plans, as well as addresses some common concerns, such as how to define a batch for a continuous process. The document looks at continuous manufacturing throughout the product lifecycle: for new products and post-approval changes.

	In an FDAVoice blog post on Sept. 11, 2017, FDA announced that it is seeking industry input on continuous manufacturing practices, including the C-SOPS best practices guide (2). Industry members have been developing continuous manufacturing technologies for their own processes, and FDA wants to develop common guiding principles building on this progress. “Given these emerging variations, FDA’s goal is to provide a framework of principles that clarify our expectations, while still encouraging companies to innovate and implement continuous manufacturing. We are talking with industry and are also helping lead this conversation on a global level by engaging our foreign regulatory counterparts regarding the development of clear regulatory standards,” said Michael Kopcha, PhD, RPh, FDA’s director of the Office of Pharmaceutical Quality, Center for Drug Evaluation and Research (CDER), in the blog post (2). The 

	An example of recent industry installations of continuous manufacturing equipment is at Pfizer’s Freiburg, Germany manufacturing site; the company broke ground for a PCMM (Portable, Continuous, Miniature and Modular) facility (a technology from the Pfizer, GEA, G-CON Manufacturing collaboration) and opened a continuous solid-dosage manufacturing facility in May 2017 (3, 4). In this continuous system, the three production steps of supplying, feeding, and mixing are linked together; two feeding systems from Coperion K-Tron use gravimetric twin-screw feeders with automated control, noted the supplier (4).    

host an industry conference on continuous manufacturing

 that is open to the public. On Oct. 16, a “mini course” designed to introduce continuous manufacturing will provide a general introduction to product and process design, implementation, process control, and regulatory considerations. The C-SOPS team will also present some of the research they have been doing in continuous solid-dose manufacturing. On Oct. 17, the C-SOPS team will run workshops on various topics and will introduce the soon-to-be-launched New Jersey Continuous Manufacturing Institute (NJCMI), a collaboration between Rutgers University and The New Jersey Innovation Institute. NJCMI will help companies implement continuous manufacturing for both solid dose and biological systems.

	1. C-SOPS Regulatory Working Group for Continuous Manufacturing, “Current Recommendations for Implementing and Developing Continuous Manufacturing of Solid Dosage Drug Products in Pharmaceutical Manufacturing,”(June 2016) 

http://docs.wixstatic.com/ugd/0da418_e51f1cf51ee248e09eead3166a554a72.pdf

, accessed Sept. 14, 2017.
	2. M. Kopcha, “Continuous Manufacturing” – Common Guiding Principles Can Help Ensure Progress,”(Sept. 11, 2017), 

https://blogs.fda.gov/fdavoice/index.php/2017/09/continuous-manufacturing-common-guiding-principles-can-help-ensure-progress/

, accessed Sept. 14, 2017.
	3.  A. Shanley, “PCMM, The Next Generation,” 

 (Sept. 7, 2017), accessed Sept. 14, 2017.
	4. Coperion K-Tron, “Feeding systems for continuous production at Pfizer Manufacturing Deutschland GmbH,” www.coperion.com/en/news-media/newsletter/2017/pharma-in-focus-edition-012017/feeding-systems-for-continuous-production-at-pfizer-manufacturing-deutschland-gmbh/, accessed Sept. 14, 2017. 

Articles

Support from FDA, a best practice guide, collaborative research, and new facilities signify progress in solid-dosage continuous manufacturing.  

Continuous Manufacturing Presses On

In manufacturing drug tablets, granulation may be performed prior to the tableting step to improve a powder’s flow and compaction properties. An alternative to traditional batch granulation for continuous tableting is continuous granulation using a twin-screw extruder. “We continue to see demand in the pharmaceutical industry to switch from batch to continuous manufacturing, as pharmaceutical manufacturers recognize that its benefits include reduced costs, smaller facility footprints necessary, and minimal loss of material and API,” notes Dirk Leister, technical marketing manager, process and pharma extruders for Thermo Fisher Scientific.

	Another benefit of continuous manufacturing is flexibility of scale, as in many cases the equipment can be run for a longer time period to produce a larger amount of material instead of using larger equipment. Scale-up from laboratory to commercial scale, however, may still be required. Thermo Fisher Scientific, which manufactures twin-screw extruders for pharmaceutical development and manufacturing, is in the early stages of developing a model to support customers engaged in twin-screw granulation scale-up projects. Pharmaceutical Technology spoke with Leister about considerations for scaling up a twin-screw wet granulation process.

When scaling up a wet granulation process, what product endpoints must be the same in the laboratory and commercial scale, and how are these best measured?

Particle size and particle size distribution are critical parameters, as they influence the tablet properties as well as the drug release profile. These parameters are critical quality attributes affecting the final product. They play an important role in scale-up from development and small-scale runs to full production.

	Traditional batch granulation methods use established offline analytical methods to determine these parameters. A recognized analysis to determine the particle size distribution is the sieve analysis. Continuous granulation processes using twin-screw granulation require online, process analytical technology (PAT) tools to deliver comparable results. Optical methods have been proven to characterize the continuous granulation process very well and can therefore be used as PAT tools in continuous processes.

	Another critical parameter is residual moisture in the granule after drying, as this influences the processability of the granule in the final tablet and API distribution in the granule and the tablet itself. This parameter is typically monitored using inline, near infrared (NIR) spectroscopic methods.

One of the advantages of a continuous, twin-screw process is the ability to quickly change parameters and perform designed experiments to define a process window. What are the typical parameters that must be considered for a twin-screw wet granulation process? Which of these factors are critical for scale-up?

 Twin-screw granulation has been identified as a viable option in today’s drug formulation marketplace, and it has been validated in a variety of papers and publications that discuss the influence of different process parameters on the critical quality attributes of the final tablet. Most of these papers, including those based on research and experiments conducted by Thermo Fisher Scientific, emphasize that the influence these parameters have on the final product is very much dependent on the specific drug formulation.

	Particle size and distribution is affected by the liquid-to-solid (L/S) ratio. The twin-screw granulation process typically reaches a steady state quickly after the L/S ratio is changed, which means that process parameters can be observed as the extruder is running, saving a considerable amount of time in process development or the quality control process.

	Twin-screw granulation offers a reliable, effective way to tailor particle properties by changing process parameters such as screw speed and throughput. In addition to the screw design (the sequential arrangement of conveying and mixing zones within the screw setup), screw speed determines the mechanical energy input and therefore influences the agglomeration process and particle break-up. The filling level inside the extruder screw determines the probability of particle–particle interaction and is also an important factor in the formation of agglomerates. All of these critical parameters require observation during process scale-up (i.e., to a larger extruder) and/or scale-out (i.e., to multiple extruders of the same size).

 What should be considered when scaling up a process from a smaller diameter twin-screw extruder to a larger one?

 A chief advantage of continuous processes is that they are time based rather than volume based (as is the case with batch processes). When a greater quantity of product is needed in a batch process, a second or successive batch must be run-which may entail some batch-to-batch variation. In a continuous process, however, a greater quantity can be produced by simply running and monitoring the process for a longer time. Throughput on the same scale also has quite a wide range. For a lactose-based formulation, we ran a process on a 16-mm extruder from 1 kg/h up to 15 kg/h with consistency in the critical quality attributes of the final granules. Scale-up is, therefore, not always necessarily the first and only option to increase the output of a twin-screw process. Additionally, when looking at the lifecycle of a drug product, it is not always necessary to produce with full capacity. A second twin-screw granulation unit at the same scale can be used to double the output and bridge the time when really high amounts are requested in a relatively short period of time.

	Having said that, in an early R&D stage the availability of material is usually limited, therefore experiments on a small scale, such as an 11-mm screw-diameter, can help to save a significant amount of material and development time. In a typical scale-up project from development to production, each extruder should exhibit similar machine geometries. Parameters such as the inner to outer diameter ratio of the screws, length to diameter ratio of the barrel, and the geometry of individual screw elements help to transfer process parameters from small scale to the production scale. If the small-scale process is robust and stable, a direct scale up from R&D to final production size (e.g., 11 mm to 24 mm or even 36 mm screw diameter) should easily be accomplished. It is not necessary, nor does it make economic sense, to go from one scale-up step to the next (i.e., from 11 mm to a larger extruder, such as 16, 24, or 36-mm diameter) until the project’s final output is determined.


	Vol. 41, No. 9
	September 2017
	Pages: 30–31

	When referring to this article, please cite it as J. Markarian, " Scaling Up a Continuous Granulation Process," 

Continuous twin-screw granulation offers several options for increasing production scale. Thermo Fisher Scientific explains factors to consider in scale-up projects for manufacturing oral solid-dosage drugs. 

Scaling Up a Continuous Granulation Process

	Cyber attacks on major companies in June 2017, including US-based pharma company Merck & Co. (1), have highlighted the importance of cybersecurity for every part of a company, including manufacturing. Interconnected operations and manufacturing execution systems, while beneficial, do create more connections that could be compromised, noted Mark Cristiano, Network and Security Services business development manager at Rockwell Automation (2).

	A “defense in depth” security approach, as recommended in the International Electrotechnical Commission (IEC) 62443 standard series, uses multiple layers of protection including policies and procedures as well as protection of networks and devices using tools such as anomaly-detection software and authentication software (3).

	“No single security product, technology, or methodology can be expected to contain cyber threats on its own. Rather, a holistic security approach should be the priority, following industrial automation and control system (IACS) security standards, including IEC 62443 and [National Institute of Standards and Technology] NIST 800-82” (4), says Gregory Wilcox, Global Technology business development manager at Rockwell Automation.

	Information technology (IT) and operations technology (OT) engineers should work together to build layers of defense, using diverse technologies, at multiple levels of the IACS, says Wilcox. “Neither side can effectively defend against cyber threats on their own. Protecting operations should include limiting physical access, hardening devices and computers, persistent monitoring through traffic inspection (i.e., detect), and segmenting (i.e., zoning) the IACS network via industrial firewalls (i.e., conduits) and virtual local area networks.”

	Assessing risk and understanding your company’s vulnerabilities, including having an updated inventory of systems, networks, and dataflows is a first step, notes Martin Kunz, product and business development manager, Plant Security Services, at Siemens. Raising awareness of cybersecurity throughout the company is also key. “Criminals look for targets, and many attacks start with a human error that lets something in,” says Kunz. He notes that training programs that give examples of possible scenarios are simple yet effective in raising awareness and empowering personnel. Controlling access, using security technology, and being prepared to respond to an incident are other important aspects of cybersecurity.  Security is not a one-time action, notes Kunz; monitoring is a continuous measure. Siemens now has three Cyber Security Operation Centers (in the United States, Portugal, and China), which are part of the company’s Plant Security Services for continuous surveillance of industrial facilities. If this monitoring detects cyber threats, experts issue a warning and coordinate countermeasures. These services are suited for process control systems used in the pharma industry, such as Siemens Simatic PCS7 or similar environments, says Kunz.

	“Threat awareness is everyone’s job,” says management and technology consulting and engineering services firm Booz Allen Hamilton (5), which suggests that security should be part of everyone’s work practices. The firm suggests that another key component is using privileged account management to make “superuser” or administrator accounts more secure.

	“The requirement to enable remote access and data sharing between OT and IT networks is now paramount,” adds Shmulik Aran, business leader for Honeywell's Security Operations Center. “While in the past, ‘security through obscurity’ was the norm, these days, pharma cyber security teams and manufacturing engineers … must cover the basics first. A secure remote access platform is essential.”

	Having an automated inventory of network assets is crucial for managing all connected devices and determining whether they are secure. “Pharma engineers should be aware of the existence, status, and compliance of every network connected device,” says Aran. “Malicious actors need only a single-entry point into the OT network to attain their goals. Employees shouldn’t be viewed as ‘weak links;’ instead, they should be actively trained and considered as a valued line of defense.”

		H. Shaban and E. Nakashima, “Pharmaceutical giant rocked by ransomware attack,” (June 27, 2017), 

www.washingtonpost.com/news/the-switch/wp/2017/06/27/pharmaceutical-giant-rocked-by-ransomware-attack

		M. Cristiano, “Addressing Security Risks in Connected Operations,” 

www.pharmtech.com/addressing-security-risks-connected-operations

Industrial communication networks–Network and system security

Framework for Improving Critical Infrastructure Cybersecurity 

		Booz Allen Hamilton, “Business Insights: 5 Facts about Cyber Security for Pharmaceutical Companies,” 

www.boozallen.com/content/dam/boozallen_site/ccg/pdf/thought_p/5-facts-about-cyber-and-pharma.pdf

Everyone from IT departments through to manufacturing line personnel should be aware of cybersecurity threats and how to prevent attacks. 

Managing Manufacturing Cybersecurity

A topical drug is typically a semi-solid formulation and may be a gel, cream, lotion, or ointment. Other topical dosage forms (e.g., powders, sprays, and solutions) are beyond the scope of this discussion. A quality-by-design (QbD) approach can be used to develop an understanding of the process and identify process parameters that will affect the quality of the product. 

 spoke with Jeffrey S. Reynolds, associate director, Pharmaceutical Sciences, at Tergus Pharma, a pharmaceutical research, development, testing, and clinical manufacturing company specializing in topical drug formulation and in using QbD for drug product design, about what to consider when developing a manufacturing process for topical drugs.

What are the key considerations for manufacturing of a topical drug? 

A suitable process can be tricky to develop for a semi-solid product, particularly in the early stages of development when the product and process may not be understood fully. The first aspect of deciding how to proceed with manufacturing is the type of semi-solid dosage. A cream or lotion will require a different approach for manufacturing than a gel or ointment. The type of mixing, the need for side vessels, heating, and cooling are all aspects essential to identifying the appropriate starting point for process development and subsequent technology transfer for scale up. 

	In general, one must consider a number of process parameters and material attributes to determine criticality and associated acceptable ranges for those critical parameters. Some parameters of interest are process temperature, heat/cooling rates, order of addition, mixing type, mixing speeds, mixing times, level of batch in tank, vacuum usage, inert atmosphere, and so on. There is no one set of parameters that will be important for every type of batch. For each product and process, its design space requires a comprehensive understanding of the critical process parameters (CPPs) and critical material attributes (CMAs) as they pertain to critical quality attributes (CQAs) of the drug product. Only then can the quality of the technology transfer and end product be guaranteed with a reasonable degree of confidence. 

 When designing a manufacturing process for a topical drug, what are some examples of CQAs and CPPs?  

The pre-development phase of drug product development will establish the quality target product profile (QTPP). The QTPP defines the desired end-product characteristics. These characteristics may include disease state to be addressed, dosage form, appearance, aesthetic qualities, color, viscosity, container/closure, drug concentration, dispensing configurations, pH, and microbial considerations. The preceding list is not intended as a complete or comprehensive listing of all attributes, but represents many of the quality attributes that the drug product developer would consider as part of the QTPP. Not all of these characteristics ultimately will be critical. However, the QTPP starts the process and helps to ensure a development program aligned with the desired end-product. Many, but not all, of the attributes identified in the QTPP will become CQAs. The criticality of a particular quality attribute will arise during the development phase as the understanding of the product and process becomes more comprehensive and complete. 

	Often, the initial QTPP will evolve and the final QTPP may not be exactly the same as the original one. It is a work in progress and intended to be dynamic document that facilitates interaction between R&D and marketing/sales. As the product development moves into understanding the process, the QTPP becomes the guiding light in identifying which process parameters are critical. Some of the typical process parameters to consider are mixing type, mixing speed, mixing time, temperature ramps, need for nitrogen or argon blanketing, UV light protection, and so on.  Again, this list is not comprehensive, but it represents many of the key process parameters that may be critical to the final drug product quality. 

 What challenges does raw material variability present, and how can these challenges be addressed?

Raw materials or excipients in a semi-solid drug product can be some of the more challenging parameters to evaluate. On the surface, it would appear that a given material that meets the 

 monographs should be adequate to provide an equivalent effect in the drug product, but this is not necessarily true. In many cases, one 

excipient is as good as another. Depending on the excipient, however, the specific supplier of a material may be a critical attribute. Additionally, potential CMAs can include where a specific test performed on the excipient falls within the acceptable range. In other words, for a material that routinely has been used at the upper end of a specific test range, it may not be suitable to use a lot of material that comes in at the lower end of the specification range. 

 monographs do not contain every critically relevant test for the material and how the material will behave in the drug product. Oftentimes, the design space analyses during development will reveal additional CMAs beyond the specific compendial requirements. For example, as many semi-solid excipients are derived from fatty alcohols and fatty acids, the chain length distribution may influence the performance of material in the drug product, even to the extent of resulting in an unacceptable product if the chain length shifts to either the shorter or longer distribution. A clear example was the pastillation of polyoxyl-2 stearyl ether. The original form (block hot pour) gave acceptable product, but the direct substitution of the pastillated form resulted in poor emulsion stability.  Both met the requirements of the 

, but only the original block form was acceptable in the cream product. 

What are some of the considerations for stability during storage and for stability testing? 

Drug product stability is guided by International Council for Harmonization requirements. Typically, samples are stored at a variety of conditions dependent upon the intended long-term storage condition of the product. In other words, if the drug product is intended for room temperature storage while on shelf, the stability study likely will have samples stored at 25 °C/60% relative humidity (RH), 30 °C/65% RH, and 40 °C/75% RH. These conditions are, respectively, the so-called real time, intermediate, and accelerated conditions for most stabilities. Other conditions relevant for alternative storage (refrigerated, frozen) will have a different set of conditions representing the real time, intermediate, and accelerated storage. 

	The intervals chosen for testing typically include 1, 3, 6, 9, 12, 24, and 36 months. Additional intervals often are included in the design to provide enhanced statistical and regression evaluation to assist in setting the initial expiry term of the drug product. Furthermore, some studies, particularly early in the development phase, may proceed only to the three-month interval. 

	Once the stability schedule is defined, selection of the testing requirements follows. At a minimum, the CQAs should be considered as part of the stability testing requirements. Early development programs may evaluate only the active pharmaceutical ingredient in the drug product for the purposes of screening out unacceptable dosage prototypes. 

	Once a product moves to the preclinical/clinical stage, the stability program will include all tests that are stability indicating, that is tests that directly reflect those characteristics that will limit the expiry term of the product. Typically, these include the active ingredient, related substances, viscosity, pH, within container content uniformity, and any ancillary stability indicating tests.

What are some key considerations in scaling up to commercial manufacturing?

The scale up and technology transfer of a semi-solid drug product can be fraught with pitfalls and challenges. There is no one size fits all (or even most). Many of the challenges in scale-up arise from an inadequately understood product or process, more specifically the CMAs and CPPs. A semi-solid drug product that has well defined CMAs and CPPs typically has less challenges on scale-up. Furthermore, when encountering challenges, this knowledge of CMAs and CPPs gives the manufacturing team an enhanced chance of successfully overcoming the challenges. Problems encountered during the development phase along with the design space analyses gives a better understanding of how the materials and process behave and their effects on the product performance. This is not to say that statistical experimental design is the answer to everything. A well-defined and understood product and process design space gives the best chance of overcoming any challenges during technology transfer and scale-up. To enhance the chances of getting the right product on the first attempt, one must ensure the CMAs as identified during the development program are matched or demonstrated as equivalent. Using the same suppliers for each of the excipients is a good starting point. The next step is to use the same type of manufacturing vessels as used in the design space work, but this is not always practical. Many contract manufacturing organizations (CMO) have only one or two types of equipment capable of producing semi-solids. Selecting a CMO that has the most similar (or identical) equipment will give the best probably of success on transfer. But what does one do when the equipment used in development is not available at commercial scale? Selecting a manufacturing unit that has similar mixing styles to what was used in the development program is the next best path forward. Having an awareness of where the product will go for commercial manufacturing helps the development team to design a process suitable for the intended CMO. None of these challenges should be insurmountable provided the development scientists, formulators, and engineers have done a thorough job of characterizing the product and process. 

:
	When referring to this article, please cite it as J. Markarian, "Using QbD in Topical Drug Manufacturing," 

Characterization of the product and process is key for process development and scale-up of topical drug manufacturing using a QbD approach.

Using QbD in Topical Drug Manufacturing

 Anniversary issue, the editors interviewed biopharmaceutical industry experts about the biggest changes the industry has seen in the past 40 years and the challenges still to be addressed (see “

The New World of Biopharmaceutical Manufacturing

” in the July issue). Here, these experts share their perspectives on the advantages of single-use (i.e., disposable) technology and on some of the changes the industry is seeing in biopharmaceutical facility design.

 spoke with Eric Langer, managing partner at BioPlan Associates; John Boehm, chairman of the Bio-Process Systems Alliance (BPSA) and Colder Products Company Bioprocessing Business Unit manager; Parrish M. Galliher, chief technology officer, Upstream, GE Healthcare Life Sciences; Sabrina Restrepo, associate director in the Sterile & Validation Center of Excellence, Global Technical Operations at Merck; Helene Pora, PhD, vice-president, Single-Use Technologies, Pall Life Sciences; Eva Heintz, global market manager, Healthcare, at Solvay Specialty Polymers; and, for facility design, Par Almhem, at ModWave.

 What has been the biggest advantage of single-use systems for biopharmaceutical manufacturing to date?

 Single-use technology saves lives, saves money, and saves the environment. The flexibility and reliability of single-use technology enable drug manufacturers to develop new therapies more quickly. Single-use technology lowers capital expenditures for facility construction and improves operational costs by increasing process flexibility, delivering faster campaign turnover and higher product yield. Single-use technology consumes less water, utilities, and chemicals with a smaller carbon footprint than traditional stainless-steel processing, creating a greener manufacturing platform. All these advantages demonstrate the potential of single-use technology in maintaining or improving sterility assurance and the quality of final drug product.

 In my opinion, the biggest advantage single-use systems have brought to biopharmaceutical manufacturing is flexibility. Now, it is possible to create sterile, closed systems with ready-to-use or steam-sterilized components that can fit into a diversity of facilities and allow for faster implementation and manufacturing times.

 In many cases, the biggest advantage is the increased speed to market for products manufactured using single-use systems. Single-use systems allow for more flexibility in development; less time and resources are spent in cleaning and validating activities, which therefore increases speed to market.

The biggest advantage of single-use technology remains the absence of cleaning and cleaning validation-critical to the operation of traditional stainless-steel systems-which saves time and money. And because you are replacing the product contact layer every time the equipment is used, you remove the risk of contamination from previous batches. Additionally, single-use systems provide greater flexibility in footprint, at all scales-users can arrange and rearrange equipment as needed. 

The benefits of single use continue to expand and unfold as the industry applies it more extensively. The benefits compared to stainless-steel facilities include reduced capital cost, reduced facility footprint, and no steam-in-place (SIP) or clean-in-place (CIP) facilities. Reduced time to build allows delaying the decision to build. Faster turnaround between batches, faster turnaround between different products, and reduced chance of cross contamination between different batches are benefits that also enable multi-product manufacturing.

 Annual Report of Biopharmaceutical Manufacturing continues to show consistent trends in single-use device adoption. The top three critical reasons given in the 2017 survey, which are driving the implementation of single-use devices are:

		a reduction in capital investment in facility and equipment

	Other factors include: ‘reduced time to get facility up and running,’ ‘decreased risk of product cross-contamination,’ and the ‘flexibility of a modular approach.’ Essentially, single-use devices are being increasingly seen as strategic tools to reduce costs and speed up both operations and facility construction.

 What have been the most significant changes in facility design for biopharmaceutical manufacturing in the past 40 years? Past five years?

Since the early 1980’s, biomanufacturing facility design has historically been dependent upon the level of segregation and separation across processes. These designs take into account flow patterns for the product, materials, operators, and waste; they are designed to ensure protection of the product, and they have been complicated by open (i.e., exposed to the environment) processing operations. To achieve this protection, the process is spread across multiple cleanroom suites with multiple heating, ventilation, and air conditioning (HVAC) zones. 

	In contrast to simpler microbial or yeast-based facilities, mammalian cell-culture facilities require additional considerations for clearance of potential virus and aerosols across the process. Virus reduction by the process steps from cell culture to bulk drug substance (BDS) is so high (10–20 logs) that a minor upstream aerosol or spill could cross-contaminate the BDS. As a result, mammalian cell-culture facility design requires more complex, multiple cleanroom segregation and separate HVAC systems. 

	In the past 5–10 years, cleanroom facility layout, design, and operation costs have come under new scrutiny as manufacturers continue to hunt down inefficiencies and reduce costs. Cleanrooms are expensive to build and maintain, and they come with high gowning and labor costs. In the past 10 years, better designed closed systems and single-use technology have become more popular. Truly validatable and robust closed systems potentially require less stringent cleanroom environments or isolators and could relieve segregation requirements from upstream to downstream operations.

	Because of these trends, open architecture facilities (or ballrooms) are being considered more often to cut capital and operating costs, with an acceptable low risk of adulteration of the product. Implementing single-use is easier in ballrooms as it facilitates the logistics of carrying in the single-use assembles and carrying them out after the batch is complete.

	The rebirth of modular facilities is another result of the trend towards single-use manufacturing, because the modules lack the expensive stainless steel piping and infrastructure. As a result, modules are simpler, lighter, and cheaper to build and ship to the facility location.

 A number of significant changes have occurred during the past 15 years.  While not an exhaustive list, the following are some of the changes I consider most significant:

		Use of isolators limiting the requirements on cleanrooms while reducing risk of contamination, thereby improving product quality

		A move to single-use and closed systems, reducing requirements on the facility as well as utility supply, while increasing flexibility in operation and lowering investment cost

		An increasing focus on flexibility and efficiency, rather than on capacity, which was the primary focus of facility design in earlier years

		Globalization (building in low cost areas) and, increasingly, market-driven localization to build in-country-for-country production

		An increasing use of modular systems (process skids, modular cleanrooms, and modular suites and buildings).

	A key driver for these changes has been cost. For a long time, the challenge in biopharma manufacturing was capacity to manufacture a growing number of blockbuster products. The key was to supply the market and cost was the secondary priority. The increasing cost pressure on pharmaceutical companies has completely changed this, and cost is now a major factor. While maybe not a dominant driver, regulatory changes are influencing how facilities are being designed and built; the increasing use of isolation technologies is a good example of this influence. Moving forward, regulatory agencies are increasingly supporting continuous manufacturing.

	Technology, market, and political trends are also drivers of change. Single-use systems, isolators, and modular systems are all technology improvements that have significantly contributed to this change. Blockbusters are giving way to smaller-volume products, increasing the need for flexibility. And with dramatically increasing yields in biologics drug substance manufacturing, the need for the ‘mega-factories’ has been significantly reduced. In addition, many countries are requiring an increasing share of products to be manufactured locally.

: What types of design do you expect will be used for new facilities in the near future?

: I think the trend towards smaller, more flexible, often modular, facilities will continue. Trends towards more potent products, increasingly personalized medicine, and new technologies (e.g., continuous manufacturing) will continue to drive the need for speed and flexibility. Some production systems will likely even be at bench-top scale. At the same time, we will likely see a few (but only a few) large-scale facilities being built.

	An interesting question is how the continued consolidation will impact these trends. Will the focus be on retrofitting existing assets (which seems likely) rather than building new facilities? That would mean that innovative ways of refurbishing and repurposing existing facilities could play an important role.

Smaller closed system and single-use facilities will be more abundant as in-market, for market distributed manufacturing spreads across the globe. Increases in efficiency to reduce costs and drug prices in emerging territories will further reduce scales as high-productivity technologies and continuous processing are applied more extensively across the process.

 How do you expect facilities to increase capacity (e.g., mobile manufacturing pods/trailers, continuous manufacturing, modular facilities)?

We see companies considering all of the above when planning their 5–10-year horizon. Scaling out (adding multiple lines of the same scale) is becoming a more popular way to add capacity because it reduces up-front capital risk and avoids scale-up risk. It can be added when the need arises, which allows companies to build the right size at the beginning and grow (or not) as the market grows.

I think we will see a wide range of alternative solutions. For larger-scale production, continuous manufacturing has significant advantages and will likely be replacing traditional batch systems. For small-volume products (with individual doses as the extreme example), the trend will likely be towards modularity, repeatability, and short cycle times. Operational efficiency will be even more crucial.

The advantages of single-use systems become clear as they become more broadly implemented.   

Single-Use Technologies Transform Biopharmaceutical Facilities and Manufacturing Equipment

Without question, biopharmaceutical manufacturing has changed dramatically since 1977, when it was in its infancy. The ball really began rolling 20 years ago and has picked up speed in the past five years. Without question, single-use (i.e., disposable) technology has been one of the most significant changes. Advantages of single-use technology include greater flexibility, reduced resources for cleaning and cleaning validation, and faster turnaround between products and batches, resulting in reduced capital costs and increased speed to market. Single-use technology has also precipitated changes in upstream and downstream processing. 

spoke with Eric Langer, managing partner at BioPlan Associates; John Boehm, chairman of the Bio-Process Systems Alliance (BPSA) and Colder Products Company Bioprocessing Business Unit manager; Eric Isberg, director of Life Sciences, Entegris and BPSA Board Member; Parrish M. Galliher, chief technology officer, Upstream, GE Healthcare Life Sciences; Sabrina Restrepo, associate director in the Sterile & Validation Center of Excellence, Global Technical Operations at Merck; Helene Pora, PhD, vice-president, Single-Use Technologies, Pall Life Sciences; Peter Levison, senior marketing director, Downstream Processing, Pall Life Sciences; Fritjof Linz, vice-president, Purification Technologies, Sartorius Stedim Biotech; and Eva Heintz, global market manager, Healthcare, at Solvay Specialty Polymers about advances the industry has made and the challenges that remain.

 What have been the most significant advances in single-use systems for biopharmaceutical manufacturing in the past 40 years? 

 Over the past 40 years, single-use systems have moved from simple blood and intravenous bags to simple media and serum containers, and to highly engineered, complex devices that are now mainstream technologies in bioproduction. Over the past five years, these devices have steadily made progress in bioprocess operations as their scalability has increased.

 In the past five years, new advances include an increase in closed systems and in larger-scale, higher-throughput, high-duty applications, such as microbial fermentation and centrifugation. Single-use sensors have been developed for a variety of process parameters for downstream steps such as chromatography, tangential flow filtration, direct filtration, and fill/finish, as well as for smart mixers for measuring parameters such as temperature, PH, and conductivity.

 In the past couple of years, we have seen just about every bioprocessing technology become available in a fully single-use format. Companies are implementing end-to-end single-use platforms for monoclonal antibody, antibody drug conjugate, and vaccine production. Flexible facilities are likely to become an important part of large biopharma’s production network and allow much needed agility in operations. 

 I think the biggest advance in single-use technology in the past 20 years was the development of three-dimensional bags, which opened the door for large-scale mixing and cell-culture manufacturing. The industry was able to scale up volume while also creating systems equivalent in shape and volume to stainless-steel vessels. Equivalency is important because much of the engineering in areas like mass transfer was performed in stainless steel.

 In the past 20 years, the sentiment has gone from, ‘why use/trust these systems’ to ‘how do we best optimize/leverage these systems.’ Overall, the ability of single-use technologies to offer sterile connections and operate a closed system, while still maintaining flexibility, has been a game-changer. In the past five years, we have seen the technology go past acceptance to start maturing, with a range of market options and sizes to accommodate various needs. 

 First used for media and buffer prep, single-use manufacturing now applies from inoculum to final formulation and filling. An initial focus on small-batch clinical trials has expanded to full-scale cGMP commercial production. More recently, drug manufacturers are using fully closed systems to make multiple drugs in large ballroom suites.

 The evolution of single-use containers from several decades ago to today’s gamma irradiation-stable bioreactors has been one of the most significant transformations; it was the impetus to move all other components to single use to close the loop. In the past five years, we have seen many advancements in sterile connectors and sensors that are gamma irradiation-stable and non-ion migrating.

 What are the most significant challenges that remain for fully optimizing single-use systems?

 There are still challenges to single use in the final fill/finish and storage. From upstream to downstream, single-use components are gaining traction in development and use. Fill and finish technology still has room to grow, including the delivery systems of biopharmaceuticals.

 I continue to hear that one of the biggest challenges is consistency and optimization of the materials used to manufacture single-use systems. Materials of construction have changed little in the past 20 years, with polyethylene and silicone dominating. I see the industry moving towards advanced materials like fluoropolymers, which solve most if not all of the challenges posed by other materials.

 High-pressure resistant, high-temperature resistant, solvent resistant, better, and more extensive sensors and smart films are needed, along with systems that enable high-G centrifugation, elimination of seams for bags, and larger connectors for higher flow rates.

 Single-use systems need to prove themselves to be a well-understood and robust technology. That might imply driving toward standardization from different perspectives: designs, interconnectivity, technical qualification packages, certificates, manufacturing practices, and product lifecycle management aspects (from user requirement specifications to management of supplier change notifications post-implementation). The establishment of industry standards such as ASTM E3051-16 or the ongoing joint efforts between the BioPhorum Operations Group (BPOG) and BPSA definitely contributes to move toward standardization. Being able to provide consistent information from drug manufacturers to health authorities around the globe will ultimately favor the prompt launch of more medicines to meet the needs of many patients.   

	Two other aspects to be considered are a broader spectra of integrated process analytical technology tools that can interface with many of the control systems available in the market and ergonomic designs or solutions for safe use by operators.  

	Organizations are setting more aggressive environmental goals, which will drive initiatives to show that single-use systems are environmental-friendly. Since the implementation of single-use systems involves a partnership with suppliers, robust and transparent supply chains to the customers are critical.   

 The industry still has more work to do to ensure all technologies are fully compatible with biological systems. Single-use systems must be tested extensively to ensure that their materials of construction do not inhibit cell growth or release chemicals into the product stream during bioprocessing. Biomanufacturers repeatedly cite the robustness of single-use technologies as being a concern, and suppliers need to support their clients by helping improve process integrity. Most significantly, biopharmaceutical companies need vendors to commit to providing a high level of assurance of consistent supply with robust supply chains and highly characterized processes and raw materials. 

 The industry’s greatest challenges are driving down drug costs to improve global accessibility and more quickly developing new therapies. Single-use technology plays a vital role in addressing these high-level opportunities. We must drive continuous improvement in education, standardization, and technology. Industry stakeholders (e.g., suppliers, users, regulators) must continue to exchange expertise and knowledge. Collaboration between stakeholders will also be critical to navigating the potentially conflicting goals of advancing standardization and technology innovation. 

 Although single-use systems have made great inroads at clinical scale, the advances at larger scale have been slower. Over the past eight years, the reasons biomanufacturers give for not expanding their use of disposables have been relatively consistent. Top concerns are the potential for breakage of bags/loss of production materials and leachables and extractables (L&E) issues. Part of this persistent concern for L&E issues is the increased use of disposables, which, in turn, has increased awareness of the uncertainties regarding related regulatory issues.

 While single-use systems are starting to mature, automation and process monitoring (sensors) remain pain points. We have yet to see how we can fully take advantage of single-use technologies with automation-even though we now have bioreactors at every size. 

 What have been the most significant changes in bioreactor technology over the past 40 years?

 We have come a long way from the first stirred tank bioreactor-even the way single-use bioreactors look has changed-with a broad range of solutions from small to large scale. As single-use systems continue to mature, we are seeing more specialized applications and new innovations. Pall Life Sciences’ square stirred tank bioreactor design has shown clear advantages over traditional round design. And Pall’s iCELLis bioreactor system is an automated fixed-bed bioreactor, designed to simplify adherent cell-culture processes using single-use technology. 

 In the past 40 years, biomanufacturing facilities were primarily built using stainless-steel technology. That technology has grown in sophistication and scale required to produce large scale quantities of biotherapeutics (up to tons/year) and vaccines (hundreds of millions of doses/year). Steam-in-place (SIP) and clean-in-place (CIP) systems, with sophisticated automation, were technological advances in stainless-steel systems to ensure aseptic operation (where needed) and minimization of soil carryover from batch to batch or product to product. 

What do you anticipate for the future of bioreactors?

 Both stainless steel and single-use bioreactors will continue to get smarter (i.e., more sensing of process parameters and product quality) and will continue to get more productive via high cell-density techniques and sub-systems. On average, they will shrink further in scale as productivities further increase and peak. They will also be integrated into recovery/purification and be operated in semi-continuous or continuous mode. The number of drugs that are produced by non-mammalian expression systems, such as yeast and microbes, will continue to climb; these will require more highly engineered microbial bioreactors. 

 Single-use bioreactors present a real solution for today’s drug manufacturer, and there is no doubt that the industry now accepts and understands this fact. Over the past few decades, we have been able to clearly establish the boundaries-for instance, we know that 2000 L is the maximum level that you can leverage the advantages of single-use. Still, users are always looking for innovative ways to optimize the flexibility of single-use technologies, and we see this resonating in approaches like parallel processing, as well as the market drive towards bringing continuous processes to the upstream.   

 What have been the most significant changes in downstream biopharmaceutical manufacturing in the past 40 years? 

 Downstream processing has changed dramatically because of the introduction of single-use technologies. Purification suites were once hard-piped with stainless steel, making them inflexible capital assets requiring utility plants to enable their cleaning and steam sterilization. Today, buffers are held in bioprocess containers and unit operations are connected with tubing. Chromatography columns can be disposable or can be replaced by single-use membrane adsorbers. In the past couple of years, single-use centrifuges have been introduced. These have application as cell retention devices as fully closed systems and can handle very high cell densities. They can also be used in viral vector and vaccine production and for the collection of the cells used in cell therapies. 

 Historically, bioprocesses were carried out with animal or plant products, introducing a great deal of challenges along the way. Today, we can express proteins in cell culture, so the approach to downstream processing is completely different. In the past five years, the biggest advances have been in the introduction, development, and general acceptance/interest in continuous downstream processes for biopharmaceutical production. 

 What challenges remain for optimizing/debottlenecking downstream separations?

 The real bottleneck is in the upstream (cell culture), which is why there is so much interest in perfusion technologies for continuous cell culture. Bioprocesses cannot be fully continuous without further advances in upstream processing. Another bottleneck can often come from the cost of goods in implementing newer downstream processing technologies; this bottleneck will likely abate over time as these technologies become fully implemented. 

 Integrating downstream processes with continuous upstream steps such as perfusion remains a challenge. There are some options available, but they are at an early stage of development. Although downstream process intensification is possible, we are still quite a long way from having the continuous flow of product through a purification train and into the vial. That is one of the challenge for downstream processing engineers over the next decade.

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	When referring to this article, please cite it as J. Markarian, " The New World of Biopharmaceutical Manufacturing," 

Industry experts discuss the single-use revolution and changes to upstream and downstream processing equipment.