Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	Creating a quality culture is a worthwhile goal for any pharmaceutical company and is supported by FDA, which wants companies to aim for "right first time". Microbiologists can play a role by helping to prevent microbial contamination incidents, rather than just investigating them after they occur. By getting involved, the microbiologist can shift the focus from compliance to quality, noted Karen Ginsbury, founder and CEO of PCI Pharmaceutical Consulting Israel and chair of IVT's Microbiology Week, in the conference's opening remarks on June 2, 2015. The cost of non-compliance is high, added Ginsbury, pointing to some recent problems related to contamination and environmental monitoring practices called out in warning letters this year. Facility design, cleaning strategies, and using investigation findings to fix problems at the source, however, can prevent microbial growth and create quality in both sterile and non-sterile manufacturing.

	Monitoring and then analyzing the resulting data can reveal problems in the making. "You may not have exceeded action levels, but if you find a discrepancy when you compare data in different production areas and compare these to historical data, you can take action anyway, such as running an extra cleaning cycle," urged Ginsbury. In the case of a contamination event, "You should 'reconstruct the crime scene' to find out what went wrong. A single root cause is seldom found, because there are often multiple contributing causes. You should fix these and then monitor further," she added.

	Monitoring and preventing contamination in a non-sterile (i.e., controlled, non-classified) process, in which limited but controlled bioburden is allowed, is actually more difficult than in a sterile or aseptic process, in which no bioburden is allowed, because aseptic processes have more stringent controls, said Chris Knutsen, associate director of analytical and bioanalytical development at Bristol-Myers Squibb, in a presentation at the conference. Crucial areas for microbial control in non-sterile manufacturing include incoming materials (e.g., APIs and excipients), personnel, and water. "Standing water is a common source of contamination in non-sterile manufacturing," said Knutsen. "Water organisms grow easily and can form a biofilm that is difficult to clean. A common problem, for example, is hoses that are stored with water trapped in them."


	Operators of non-sterile processes now have more specific directions to follow, since in 2014, USP published an informational chapter, 

 <1115> "Bioburden Control of Non-sterile Drug Substances and Products," which details risk assessments and environmental monitoring for non-sterile processes. Prior to this publication, operators of non-sterile processes sometimes used 

 <1116> "Microbiological Evaluation of Clean Rooms and Other Controlled Environments," which is an informational chapter for aseptic processes.

	In February 2015, the European Medicines Agency published a concept paper describing a revision of Annex I of the EU GMPs, which will include updates for sterile processing and adaptation to International Conference on Harmonization Q9 and Q10 documents. The revision will also specifically address non-sterile processes, noted Ginsbury.

	A Parenteral Drug Association (PDA) publication, planned for publication in 2015, is a technical report on cleaning and disinfection, said Jim Polarine, technical service manager at Steris, who serves on the task force for this report. In a conference presentation, he described components of validating disinfectants for a cleanroom. Vendors will test efficacy of disinfection against ATCC standard reference organisms, but ideally, users should test in-house environmental isolates. First, the cleanroom should be monitored for six to twelve months and organisms should be identified. From these data, isolates can be chosen for 

 testing. Knowing what flora are normally present in a facility is crucial. If something changes-a new floor, for example-the disinfection program should be revalidated, said Polarine.

	Polarine also discussed best practices for disinfection, which include ensuring appropriate contact time and testing the effect of water quality on the disinfectant. It is possible to have too much of a good thing, however. Over-use of sporicides can break down flooring or wall materials, and these damaged surfaces create places for microbes to grow, noted Polarine. Some sporicides can cause corrosion; when this occurs, the corroded part should be replaced or monitored for microbial growth.

	More discussions on these and other topics will be discussed at IVT's Validation Week in Philadelphia, Oct. 27–29, 2015. 

Articles

Presenters at IVT's Microbiology Week discussed best practices and recent guidance publications for microbial control in sterile and non-sterile pharmaceutical processes.

Microbiologists Contribute to a Quality Culture

	The US Drug Supply Chain Security Act (DSCSA), and how pharmaceutical companies can meet its serialization requirements, has been at the top of many agendas since the first phase of the law, which requires change-of-ownership data, came into effect in 2015. A crucial question is whether to implement the requirements in stages (i.e., to meet the machine- and human-readable package-code requirements for November 2017) or to look at the end goal of unit-level track and trace that will be needed in 2023. Implementation-even of today's requirements-has many technical and organizational challenges, and few companies are looking ahead, said speakers at a session on serialization at INTERPHEX 2015 (1). Companies would benefit, however, from a more holistic view, noted Joe Whyte, global serialization lead for Rockwell Automation, in a seminar on May 20, 2015 (2).

	"Looking at serialization piece by piece is inefficient and problematic because you need interoperability between all system levels for traceability," said Whyte at the seminar. "Companies shouldn't look only at legislation requirements. Instead, they should look at the business benefits and do the whole traceability project now." Benefits of traceability include real-time visibility into what consumers are buying, which allows businesses to optimize their inventory and production levels. Additional benefits include the opportunity for patients who voluntarily choose to share information with the manufacturers of the products they use to participate in patient support, patient compliance, and patient safety programs (e.g., individual notification of recalls). These benefits are being realized in other industries, such as consumer products and groceries, Whyte pointed out, noting how shoppers today receive targeted coupons at the grocery checkout based on the barcodes of their purchases, for example.

	While most countries have serialization laws, most are not yet requiring aggregation and traceability, with the exception of Brazil. "Brazil is the pilot project for the world on aggregation and traceability," said Whyte. Brazil is on the most aggressive timetable, with full traceability required by the end of 2016 and a proof of principle by the end of 2015, for which companies must test traceability of three batches of one product all the way from the manufacturing plant to the consumer. Once Brazil has a completely traceable system with more secure products going to consumers, other countries are likely to implement sooner than legislative deadlines to stay competitive, predicts Whyte.

	The equipment needed for a traceability system is available now and is being used in Brazil already, Whyte said. There are, however, some challenges to address when implementing a system. Connecting equipment (e.g., printers and machine vision) is crucial; standard, open network and communication systems, rather than custom systems, facilitate equipment interoperability, which is more flexible and subsequently easier to support, noted Whyte. Storing and accessing data are other challenges that are optimally solved using cloud storage, said Whyte. "The customer standing at the drugstore counter does not want to wait long for data to be checked. Cloud storage allows for secure high speed data movement no matter what the geographic locations."

	Choosing a standard for sharing and communicating data is another issue. FDA's draft guidance on data exchange, released in November 2014 (3), allows use of electronic data interchange (EDI); EPCIS, an electronic product code system from GS1; or web portals. Many companies in the US have chosen EDI, but EPCIS, which was built specifically for track and trace, is more flexible and may be a better long-term choice, cautioned Bob Celeste, former senior director at GS1 US and founding partner of consulting company RC Partners, at the seminar (4). For example, EPCIS is a global system that allows queries, while EDI does not, he explained.

	Another aspect is testing the traceability system. Virtual systems are a useful tool for testing without the risks of testing a real system, such as a test product accidentally reaching a consumer, said Celeste. Using software, a company can test whether the traceability system works by, for example, introducing a counterfeit drug at some point in the supply chain and testing if and when it is noticed. Scenarios such as recalled product or theft can also be simulated. "Companies are responsible for serialization data and must use it to protect patients, not just collect and store it," noted Celeste.

Pharm. Tech. Sourcing and Management enewsletter

www.pharmtech.com/serialization-deja-vu-all-over-again

		J. Whyte, "Serialization Challenges-Holistic Solution & Support," presentation at the Serialization Seminar (Iselin, NJ, 2015).	

Draft Guidance for Industry: DSCSA Standards for the Interoperable Exchange of Information for Tracing of Certain Human, Finished, Prescription Drugs: How to Exchange Product Tracing Information 

		B. Celeste, "Serialization GS1 Standards," presentation at the Serialization Seminar (Iselin, NJ, 2015). 

Although full traceability is not required by law in the US until 2023, companies could benefit from implementing it now.

Considering Full Serialization

	Continuous manufacturing for solid-dosage drugs has made significant strides over the past few years and commercial activity is increasing, as was evident at Interphex 2015 in presentations and exhibitions. Industry experts agree that continuous processing offers potential economic benefits, including reduced costs due to lower inventory and significantly increased flexibility of scale. The use of continuous processing is on the upswing because manufacturers are recognizing these economic benefits; research efforts and an increased academic focus have solved many of the initial technology concerns; and there is now greater availability of equipment, said Christine Moore, acting director in the Office of Process and Facilities at FDA's Center for Drug Evaluation and Research (CDER), in 

	Continuous processing has long received support from FDA, which has been interacting with the European Medicines Agency, academia, and industry for more than six years to advance the technology, noted Moore in a presentation at Interphex. Continuous processing aligns well with FDA's process analytical technology (PAT) and process validation guidance. Modeling and system monitoring, using PAT for example, allow for greater control, resulting in greater assurance of quality, noted Moore. There are no real regulatory hurdles to continuous manufacturing, but experience is limited, said Moore in the presentation. Experience is growing, however, and "FDA is staffed, trained, and ready to discuss," she said, noting that companies should meet early with FDA to ask questions and discuss their plans for continuous processes.

	Significant differences between batch and continuous processing are the way material flows and the measurement and control of the system, noted Moore. In continuous processing, unit operations are connected and interactions can be coupled, thus the control strategy is often different from that of batch processes. It is also important to understand the system dynamics, including how the material mixes and how it can be traced through the system, she explained. Continuous processes are typically plug flow, in which the material is mostly 'first in first out'. A disturbance in feed for a batch mixer is readily evened out during mixing, but mitigation of such disturbances in a plug flow system should be understood and modeled. "You should be measuring at an appropriate measurement frequency so you can detect fluctuations in quality and then have controls in place to make sure you have assurance of quality throughout the entire run," explained Moore in an interview.

	Process modeling is a tool that can be used to answer questions such as how material mixes. Because continuous processes are integrated, an integrated model is needed to describe the system, explained Doug Hausner, associate director at the Engineering Research Center for Structured Organic Particulate Systems (CSOPS) at Rutgers, the State University of New Jersey, in a presentation at Interphex. Flowsheet modeling tools can be used to help define a batch and validate that definition, by tracing how the material flows through the system and describing the residence-time distribution in the system. A model can also be used to do process sensitivity analysis and to optimize parameters such as output. Using models for risk assessment is key. "Models allow you to look at variations, such as perturbations in the system, and assess risk for a given product," Hausner added in 

. Modeling saves money and time by evaluating processes in a computer-modeling environment, which can then be verified in the laboratory, he concluded.

	A Pfizer, GEA Pharma Systems, and G-CON Manufacturing collaboration on a PCMM (portable, continuous, miniature, and modular) system was being promoted at Interphex. Pfizer brought the pre-assembled and prevalidated pieces of a prototype PCMM system to its facility in Groton, CT and is now getting the system up and running, said Phil Nixon, executive director for drug product technology and innovation lead for pharmaceutical sciences at Pfizer, in an interview with 

. The prototype system is designed to produce uncoated tablets, but could be modified to add other unit operations, such as coating. The concept could even be used for API synthesis or biologics, added Nixon. "An objective of this project was to make the technology broadly available to the industry," he explained. "The vendors (GEA and G-CON) are offering the equipment commercially, and Pfizer hopes that more companies will use it because that will help advance continuous processing technology." 

	Two weeks after Interphex, at a CSOPS workshop, "The Future of Advanced Pharmaceutical Manufacturing," held on May 7, 2015, representatives from pharmaceutical manufacturing, academia, and FDA gathered to discuss how to further advance continuous manufacturing in the pharmaceutical industry. A strong academic base is important for innovation, noted Janet Woodcock, director for CDER, in the keynote address. "FDA's vision for what needs to be done next to advance continuous manufacturing is closely aligned with the vision at CSOPS," commented Hausner in discussing the workshop with 

. "This vision includes a focus on process modeling and a greater scientific understanding of the process, for example." One of the next steps for CSOPS, which was spurred on by an invitation from Woodcock at the workshop, will be to put together a document to serve as input for a draft guidance on continuous manufacturing. 

Economic benefits, equipment availability, research results, and FDA support are driving progress in continuous processing.

Advancing Continuous Solid-Dosage Manufacturing

	Interphex 2015 (April 21-23) will showcase some of the latest bio/pharmaceutical manufacturing and development technology. An increasingly important segment of that technology will be second-hand equipment. As a growing number of pharmaceutical manufacturers are learning, second-hand doesn't have to mean out-of-date. Like pre-owned late-model cars or electronic devices, late-model drug manufacturing equipment is increasingly available.  Some of it is less than a year old, says Randy Small, vice-president of operations for the Americas at Liquidity Services. In some cases, equipment was purchased but never used, adds Ben Potenza, vice-president of marketing at EquipNet (exhibiting at booth #3359).

	Buying used equipment is a win/win for both buyer and seller. Buyers save money and shorten delivery time, notes Matt Hicks, COO and counsel at Federal Equipment Company (exhibiting at booth #1742). Sellers, who may have closed a facility or who no longer need a piece of equipment, can recoup some of their investment and improve their return on investment. 

 asked these experts what pharmaceutical companies should consider when exploring buying or selling used assets.

 What are the primary reasons a company might want to consider purchasing used equipment?

 One of the top reasons for purchasing second-hand equipment is the lower starting cost. Start-up companies often take this route because they want to get 'in the black' sooner, and there are a lot of start-ups around the world right now. We are also seeing an increasing number of Fortune 500 companies looking at the second-hand market as a sustainable, cost-efficient way to obtain equipment, and we are doing business with more of these large companies this year than last year or the year before. We are selling 47 out of 52 weeks of the year, with 300–500 pieces of bio/pharmaceutical equipment each week.

 The ability to save between 50-75% of the cost of new is an attractive factor. Budgets can be stretched and cash saved for additional purchases. In addition, pre-owned equipment is generally available immediately. Delivery can be made as soon as a purchase is completed, which is not always guaranteed when ordering a new system.

What types of pharmaceutical equipment are typically purchased in the second-hand market? 

 Laboratory R&D assets make up most of the pharmaceutical equipment in the second-hand market today.  Examples include liquid chromatography and mass spectrometry instruments and smaller benchtop assets, because the turnover rate is inherently higher in R&D. About 20% of assets in the market overall are manufacturing assets, typically from Fortune 500 companies, which ensures that they are well maintained and calibrated. The majority are sold in their natural environment, rather than a warehouse.

 All manner of equipment categories are sold in the pre-owned market, including laboratory instrumentation, pilot-scale and formulation machinery, packaging equipment, and plant utility assets. Solid-dose facilities purchase many fluid-bed dryers, encapsulation machines, tablet presses, and blending equipment, for example. Sterile locations might need vial-filling lines, bioreactors, autoclaves, and water-purification equipment.  Tanks are always in demand.

 For our pharmaceutical customers, we focus on processing and primary packaging equipment for all types of solid-dose and liquid pharmaceutical products, including aseptic fill-and-finish. Late-model, quality equipment is always in demand and does not last long in our inventory.

 How old is 'late-model' equipment, and what cost savings can be obtained?

 In general, we consider less than five years old to be late model, with most of it three to five years old. This equipment is desirable because it is well maintained and still current. Startup companies have a high turnover rate, so equipment from them may be one to three years old, or occasionally less than one year. For equipment in the five to eight-year range, you need to do your homework to be sure that the technology is current and that the asset will do what you need.

	The savings compared to purchasing new is typically 30-50% for the less-than-one-year-old range and 40-75% for two-to-three years old. For equipment older than three years, depending on supply, the savings can be in the 50-80% range. Buyers are finding savings a little higher than they did a year or two ago, which is partly due to an expanding marketplace with more sellers.

 The answer here really depends upon the equipment, the original equipment manufacturer (OEM), and the maintenance program. Many types of equipment can have long, productive lifespans-the year of manufacture should not always determine whether a machine is still worthy of use in production. Obsolescence for pharmaceutical process equipment, as a general rule, is when that machine is no longer fit for use in a cGMP environment or there is no support network for the equipment through in-house knowledge, the OEM, or a reliable third party provider. 

	We acquire our inventory from the top names in pharmaceutical manufacturing-companies that purchase higher quality equipment from the start, engineer it to last, and have robust fixed asset management and preventative maintenance programs supporting that equipment. This equipment is more likely to be of a higher quality and in better shape so that OEMs can provide the bulk of the support. The buyer can thus trust each purchase, and have that equipment installed and ready for production as soon as possible. Our inventory can be delivered in weeks or even days, compared with months for built-to-order equipment. 

 Ironically, 'used equipment' is often a misnomer. Many times our clients have built facilities in anticipation of a ramp-up in production that never materializes. In these cases, we are often selling equipment that has never been used but is still 'pre-owned.'  For those items that are used, their value obviously has a direct relation to their age and the state of the current new technology compared to the machine that is for sale. Most buyers that are shopping in the second-hand pharmaceutical market are looking for equipment that is 10 years and younger if there is technology involved.  However, stainless steel tanks can be much older if they are in excellent condition.

 What options would you recommend that a company consider for equipment they no longer need?

 A company should first consider redeployment within sister divisions or other locations. If the equipment is not needed inside their own company, they should consider selling the equipment. This route brings income and avoids the cost of disassembling and relocating the asset, because, typically, the buyer is responsible for moving the asset.

	The market for used equipment is booming. Sellers should find a reputable company with an online marketplace and global market of buyers to ensure they will maximize their return on the assets they want to sell.

 Redeployment should always be the first consideration for a company with surplus equipment.  Clearly, relocating an asset that you already own ensures the highest return on investment for that asset. Beyond redeployment, a facility needs to factor in the amount of time that they have to sell the item. If there is not an immediate deadline for a high-value item, selling it in a negotiated sales platform will yield the next highest level of return.  If it's more of a commodity piece or the owner's priority is quick liquidation instead of highest return, then an online auction event is the preferred channel.

 We specialize in acquiring used equipment in many different ways. Sellers can choose to sell equipment individually, item-by-item, or as a lot through a bidding process.  There are auction and consignment options available. If the equipment is needed internally, we offer an in-network redeployment program when there is a good fit. The key is to understand that the solution for surplus equipment is not 'one-size-fits-all', but to focus on how to maximize the seller’s return in combination with many different factors, including project deadlines, site constraints, removal costs and methods, and conducting the project with minimal disruptions to ongoing operations or other stresses on the facility.

 When should a company consider redeploying surplus equipment?

 Redeployment of existing equipment makes a great deal of sense because it maximizes the potential return for that idle equipment.  Redeployment puts that equipment in a place where it can produce saleable product rather than just being sold for the equipment’s own value. Additionally, the equipment history is completely transparent and records can be easily transferred without too many intellectual property concerns. 

	With that said, a redeployment program will only work if there are multiple sites in the company’s network with similar equipment requirements. There must also be a financial strategy that makes redeployments attractive to the receiving site. This strategy mainly concerns the valuation of the equipment for the receiving site (e.g., net book value or fair market value) in addition to the removal and shipping costs.

	Finally, there should be some strategic review of the transfer against a capital expenditure budget or some other identified objective.  If a transfer cannot be justified against a capital budget or, for example, as a risk mitigation strategy, these would-be assets may just go from storage in one facility to storage in another facility, where they sit inside a crate in a warehouse or take up valuable manufacturing floor space without ever making anyone any money, which is why they were made available in the first place.

Experts discuss some of the latest trends in buying and selling used pharmaceutical equipment assets.

What's Old is New Again: Wresting Value from Second-Hand Equipment

Quality-by-design (QbD) methods, which focus on using science- and risk-based approaches to design a process, are increasingly being used in pharmaceutical process development and scale-up. A goal of QbD was to reduce regulatory burden and allow continual improvement within a design space. FDA is incorporating QbD concepts, for example, in its question-based review for new drug applications (NDAs) and abbreviated NDAs (ANDAs). Professionals at a growing number of pharmaceutical companies are finding that QbD-based strategies are more efficient and help achieve the goals of getting products to market faster with less expense, reduced risk, and more consistently high quality.


	In the small-molecule drug-substance market, a trend toward outsourcing chemical development and early-stage manufacturing has created new requirements for streamlined technology transfer between companies and sites, note Steve Cropper, business development manager, and Joe Hannon, CEO, both at software provider Scale-Up Systems. “When you start to hand over reaction, workup, and isolation steps to be run at scale, often in different geographies, making a robust assessment of what is going to work becomes a priority,” explains Cropper. QbD tools allow an increased understanding of the process, which leads to a more robust and reliable process with reduced risk for scale up. “Application of QbD tools enables practitioners to ‘hit the sweet spot’ quickly,” adds Cropper. “So, even though chemistries may be getting more complex with more steps to scale-up, the right tools are enabling users to find the conditions where they can run their processes to achieve their critical quality attributes (CQAs).” This holds true for both drug-substance and drug-product manufacturing.

	“A change in scale-up strategy is identifying, characterizing, and focusing on scaling up the key drug product attributes rather than by scaling up process parameters using conventional scale-up principles,” notes Preetanshu Pandey, senior research investigator at Bristol Myers Squibb. “This strategy ensures more confidence on scale-up that, in turn, enables more development work to be conducted at small scale (i.e., minipiloting), leading to significant API savings,” says Pandey. “A part of the reason such a strategy is now possible is the introduction of new process analytical technology (PAT) tools that can provide that level of characterization, in addition to an enhanced understanding of relevant drug-product properties or key process factors that directly affect CQAs.”

	“By enabling advanced process understanding, QbD reduces the risk of batch failure or the need for rework when changes are made,” says John Groskoph, senior director, global chemistry, manufacturing, and controls at Pfizer Global Supply. “When we understand our processes more thoroughly, we are better positioned to anticipate potential risks to product quality. The concept of connecting the attributes of the finished drug product back to the quality target product profile and, ultimately, to patient needs, is the foundation for any QbD program. Challenges do remain, however, particularly with how to use enhanced process understanding to enable post-approval changes in ways that may differ from established regulatory guidance.”

	QbD approaches are increasingly used to provide a greater assurance of scale-up success with less need to troubleshoot or redesign after failure at a larger scale, says Christopher Potter, International Society for Pharmaceutical Engineering advisor and chemistry, manufacturing, and controls consultant. Using QbD approaches that incorporate a quality risk management (QRM) methodology reduces risk and facilitates scale-up. QRM involves risk identification, analysis, and evaluation to produce parameters that can be investigated to enable risk reduction in the formulation and in the process design, Potter explained in a webcast on scale-up using QbD (1). A multi-functional team (i.e., scientists, manufacturing personnel, engineers, quality assurance personnel) is crucial for QRM, said Potter, because these experts can identify the risk factors, particularly those important to scale-up, during the development phase, rather than later. The team analyzes the process using tools such as fishbone diagrams to identify CQAs and potential critical process parameters (CPPs). QRM tools (e.g., failure mode and effect criticality analysis) can be used to produce matrices to show the relative risk of each CPP on relevant CQAs. Designed experiments are conducted on the high-risk factors to try to reduce risk, and the team reiterates the risk assessment if necessary. “As evidenced in public presentations, QRM techniques are widely used by both innovator and generic companies,” Potter told 

. “There seems to be increasing use, encouraged by regulators, with, for example, the question-based review process operated in the US for generic product ANDAs.”


	PAT using online, inline, or at-line methods produces real-time results, which reduces time in scale-up experiments because decision makers don’t need to wait for off-line laboratory results before making adjustments. In addition, real-time data are more useful for troubleshooting and understanding what is happening in the process. “Rather than simply knowing that a batch failed, you know why it went wrong,” explains Emil Ciurczak, principal at Doramaxx Consulting. “The constant flow of information also helps you continuously improve your process.”

	A PAT machine-vision imaging tool for inline particle characterization can show processors, in real time, whether they are obtaining the properties they expected at scale-up. “Imaging can be used to ‘fingerprint’ a product for scale-up,” explains Luke Kiernan, technical services director at Innopharma Labs. “You can take images of spheroids or granules at a 2-kg scale, for example, and look for the same particle size and morphology at a 100-kg scale.”


	The speed and quantity of data collection from PAT, as well as high-throughput experiments and design of experiments (DOE) programs, while beneficial, can present a quandary. “A challenge for customers is to avoid drowning in a sea of experiments and data, especially when much of the data are not informative or important,” says Cropper. Multivariate data analysis software can be used to help identify which variables are important, particularly when the impact of scale-up on a process is not as well understood or is complex, as is often the case in biopharmaceutical process modeling.

	Using mechanistic, first-principles modeling, however, should be the first choice if possible, and software is available to help scientists and engineers apply fundamental principles without having to directly handle the math, says Cropper. In API manufacturing, for example, “Modeling software can quantify the effect of scale-dependent physical rates (e.g., mixing and heat transfer) on scale-independent chemistry (e.g., the rates of the main product and impurity-forming reaction steps) as well as crystallization and isolation. Linking these rates in a predictive model enables the scale-up and technical-transfer groups to visualize whether they will get the results they expect on scale-up and to select, or specify, the best equipment for their API steps. In short, it enables more confidence that scale-up will be successful in today’s accelerated development programs,” he concludes.

	Modeling technologies enable process engineers to simulate changes in the process model and develop an optimized process and control strategy without running experiments on the actual process. This strategy saves time and cost.

	Flowsheet models are process system engineering tools that can be used to improve control strategies and product quality for continuous manufacturing processes, note the authors of “

Flowsheet Models Modernize Pharmaceutical Manufacturing Design and Risk Assessment

 (2). Because the equipment in a continuous manufacturing process is integrated in an end-to-end fashion, understanding the relationship each piece of equipment has on the product is not a trivial problem. Understanding the impact process variations have in the output of the system is crucial for quality control and risk management. Flowsheet models use the individual mathematical models for process equipment to create a model representation of the integrated continuous process in order to study the system 

. Using flowsheets, the impact of process disturbances on the product properties can be simulated, which allows quantitative risk assessment and development of effective control strategies. Flowsheet models can be used for the design, control, scale-up, and assessment of continuous processes and can also help translate batch processes into an integrated continuous process.


	Continuous processing is being developed for API production, drug-product manufacturing, and, in some cases, for end-to-end production with no break between.

	“Continuous manufacturing is the way of the future,” says Ciurczak. “Drug pricing pressure is pushing manufacturers to modernize to reduce costs, and industry has reached the tipping point for using continuous processes-NDAs using continuous processes have been approved and equipment is commercially available for anyone to purchase.” 

	Optimizing a continuous process with DOE uses much less material than DOE in a batch process and can be performed more quickly, because process conditions can be changed relatively quickly. Continuous processes are easier to scale than batch processes, and, in fact, can eliminate the need for scale-up at all because the process could, theoretically, be run for a short time to obtain a small-scale volume or a longer time to obtain a larger-scale volume, with both scales using the same equipment and processing conditions. 


	1. C. Potter, “Strategies for Successful Scale-up Using Quality by Design,” Webcast (Mar. 27, 2014).
	2. M. Escotet-Espinoza et al., 

 When referring to this article, please cite it as J. Markarian, “Modernizing Scale-Up,” 

Quality-by-design tools improve efficiency in scale-up of pharmaceutical processes.

Modernizing Scale-Up

	
	A proposal for a drug-product manufacturing classification system (MCS) for oral solid-dosage forms, which would build on the idea of the biopharmaceutics classification system (BCS), was published in January 2015 (1). Written by specialists in the UK’s Academy of Pharmaceutical Sciences (APS) MCS working group, the proposal has been discussed at various industry forums by primary authors Michael Leane, principal scientist at Bristol-Myers Squibb; Kendal Pitt, senior technical director at GlaxoSmithKline; and AstraZeneca’s Gavin Reynolds. The system would gather existing knowledge and experience to categorize and describe the properties of an API that would enable manufacture of a finished drug product with a given processing route. The classification system would complement the BCS and help developers select a process for a given API and/or indicate how an API could be optimized for processing with a given route. “A common understanding of risk would help in choosing a solid-dosage manufacturing process and would provide targets for API particle engineering efforts,” said Leane in an interview with 

	The processing technologies included in the classification system are, in order of increasing complexity: direct compression (DC), dry granulation (DG), wet granulation (WG), and other technologies (OT), such as melt granulation or liquid or semi-solid-filled capsules, for example. More complex processes can handle a wider range of API properties, but may have more steps or related costs. DC, for example, is the simplest process with only mixing and compression, but unfavorable API particle size and shape may be difficult for DC to handle. MCS would aid API development that seeks to engineer API particles to enable use of the simplest process possible for a given formulation. The MCS can also provide information for negotiations between CMOs and pharmaceutical companies by providing a common understanding of API properties and what might be needed to produce a drug product.

	The MCS would also facilitate scale-up to clinical or commercial manufacturing facilities. “The MCS would help ensure that the chosen process is more robust by putting the process in the center of the design space rather than at the edges,” explains Leane.

	“If you choose the optimal process, scale-up should be easier and have less risk,” adds Pitt. “A more complex manufacturing process might have less worries about how the API will perform but more potential for troubles with scale-up. In granulation, for example, the wetting step could cause a form change; milling subjects the API to shear, and drying subjects it to heat. There are a lot more steps for something to go wrong.”

	The MCS is seen as a simplified starting point that classifies only API properties. Interactions with excipients, for example, were not included in the outline. Although excipient choice can certainly affect a formulation, the working group felt that this might add too much complexity to the system. “Companies can use the MCS to perform their own proprietary, more detailed risk analysis that would include a company’s own knowledge, preferences, and expertise based on their own therapeutic areas,” suggests Leane.

	The MCS working group plans to continue its discussions and present their ideas at the FIP World Congress of Pharmacy and Pharmaceutical Sciences (Dusseldorf, Germany, October 2015) to elicit suggestions and thoughts from industry professionals. The authors plan to subsequently publish another paper describing possible refinements to the system. 

 When referring to this article, please cite it as J. Markarian, “Choosing oral solid-dosage production processes: Could a classification system help?,” 

A drug-product manufacturing classification system (MCS) for oral solid-dosage forms is proposed by an Academy of Pharmaceutical Sciences working group.