Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	Replacing stacks of paper records with easily searched and shared electronic records has clear benefits for both the near and long term, but making the switch requires careful planning and risk management. 

 spoke with Ken Kovacs, quality business systems manager at Fujirebio Diagnostics, about the advantages of using electronic production records and the keys to successfully implementing a system.

: What are electronic production records (EPRs), and how do they relate to electronic batch records (EBRs)?

: Production record requirements are identified in various FDA regulations, such as 21 

	Part 211 for Finished Pharmaceuticals (1) and 21 CFR Part 820 for Medical Devices (2). Production records can be considered a collection of all the records required to manufacture an FDA-regulated product as well as all the records produced during the manufacturing of those products to meet specific regulatory requirements. EPRs provide an electronic equivalent to paper production records as required by agency regulations.

	The concept of EPRs has not been used as extensively in industry as EBRs. An International Society for Pharmaceutical Engineering (ISPE) special interest group (SIG), the Good Automated Manufacturing Practice (GAMP) Manufacturing Execution Systems (MES) SIG, used EPR as a more universal term to include all associated production records for both pharmaceutical and medical device industries, which is important because of the increasing overlap in these industries (e.g., combination drug-device products).  Both batch records and device history records can be considered subsets or components of production records. ISPE’s 

GAMP Manufacturing Execution System Good Practice Guide

 (4) provide appendices describing electronic production record systems and associated functionalities, such as ‘review by exception’ and electronic signatures.

	Implementing EPRs creates the ability to generate and distribute electronic records within the enterprise in a timely manner, dynamically control processes to decrease product variability, and assure product quality during production. CGMP-compliance issue investigations and their associated paper-based records may also be simplified through information derived from EPR reports. Over time, EPR systems can evolve to provide real-time product disposition and provide a database of scientific knowledge needed for process understanding and future product development.

: What have you found to be the biggest advantages of EPRs?

: Fujirebio Diagnostics’ current EPR system has saved several thousand hours of people’s time when compared to the previous, manual data-logging process and review of associated paper-based GMP reports. Paper-based logs and reports have been eliminated. Parameter data are automatically logged, analyzed in real time, and retained in a database by the computerized system. Authorized personnel are immediately notified via email in the event an adverse warning or excursion occurs with any monitored parameter, and system functionality allows us to capture personnel comments and electronic signatures by department for each event.

	Monthly departmental summary reports (SRs) are generated for ‘review by exception’ and routed via workflow software to each department for review and electronic signature approval.  The SRs are then routed to quality assurance (QA) for final review and approval. Once approved by QA, the system generates a monthly electronic SR for each department and appropriately files it for retention and future use. All data and electronic records are routinely backed up through information-technology processes and procedures.

	With this system, we now have the ability to more easily analyze equipment and process operations for a better understanding of critical process parameters and product quality attributes.

: How did Fujirebio Diagnostics go about implementing EPR?

: Our executive management team had already identified an electronic initiative as a concept for implementing electronic records. The EPR project team then identified a strong business need for this specific EPR system. A project justification and return-on-investment calculation based on implementing an infrastructure conducive to installing future applied solutions was developed for management review. Based on this strong need and justification, the project was quickly approved. Before developing an infrastructure and architecture, the project team agreed on using International Society of Automation (ISA) 

 (7) standards and models as guidance for system design.

	Personnel from the entire company were engaged to obtain their feedback and expectations for this new system. Twenty-seven individuals from all departments participated in the development of the user requirements specification (URS). This project was truly company-driven by users and management working together.

: What were the keys to successful implementation?

: Direction from executive management provided the support for launching this project and was crucial to getting this system approved. Project implementation was guided by our formal system development life cycle (SDLC) and a step-wise project management methodology that includes a risk-based approach to design and validation. The use of global standards and models greatly reduced the time needed to define a site-wide architecture and system functionality.  Once the URS was completed, a request for proposal package was developed, and leading system integrators (SI) were identified and invited to participate in our selection process. A SI providing what we identified as the best applied solution to address our user requirements was then selected. Deliverables required for each phase of our SDLC were completed as the project progressed.

	Before going live with this system, a comprehensive documentation package was completed, robust qualification testing was executed for validation, and more than 60 users were trained. Completion of system validation allowed us to move one step closer to system turnover. After formalizing a system support team and process, the system was then operated in parallel with existing, manual standard operating procedures (SOPs) for three months. Because this was the first implementation of a record system of this type, we wanted to ensure that everyone was properly trained and that everyone understood the process of generating and approving the e-records. In addition to system-level training, we included training on our e-signature and e-record SOP, which is based on 21 

 Part 11 requirements. The comparison of e-records to paper was integrated in our approach to system qualification for validation. At the end of three months, our user community was comfortable with the new system and was also eager to make the transition to e-records, after seeing how much easier it is to use compared to the time previously spent in manually logging data and reviewing stacks of paper records. Migration to the electronic record system was then made official, with manual activities relegated to a back-up role. Existing SOPs previously used for generating manual logs and paper records will now be used only if there is an operational interruption to the automated system.

	During the entire project, timely meetings were conducted with the SI and contractors, team contributors were acknowledged and thanked, and project update bulletins were frequently posted to keep all company personnel apprised of progress being made. This communication was important because the new system was a significant change that affected people in 18 different departments.

: How does the new infrastructure provide a basis for further improvements to manufacturing equipment systems?

: During initial discussions on what an electronic initiative meant to Fujirebio Diagnostics, a ‘future state’ of paperless operations was envisioned and various strategies identified to make it all happen. The infrastructure implemented with our first project was designed to provide an architecture that addresses equipment integration, data acquisition, and information management from the shop floor through manufacturing operations and up to our business systems. System hardware and software products from global suppliers were chosen to provide for easy expansion and compatibility with future applied solutions.

	Since this system was originally installed, we have doubled the number of GMP-related equipment that is being monitored, added more electronic record capabilities, and used system information to support other operations and quality processes. We are now scoping out a new project to further expand data acquisition into other areas in manufacturing with added functionality for manufacturing operations management. By implementing an infrastructure up front with capabilities to meet future needs for data management and EPRs, we now have an established step-wise strategic approach to rolling out applications that support our electronic initiative path forward.  

, Title 21, Food and Drugs (Government Printing Office, Washington, DC) Part 211, Subpart J-Records and Reports (2014).
	2. 

, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 820, Subpart M-Records (2014).
	3. ISPE, 

GAMP 5: A Risk-Based Approach to Compliant GxP Computerized Systems

GAMP Good Practice Guide: Manufacturing Execution Systems-A Strategic and Program Management Approach

ANSI/ISA-95.00.01-2010 (IEC 62264-1 Mod) Enterprise-Control System Integration - Part 1: Models and Terminology 

(Research Triangle Park, NC, 2010).
	6. ISA, 

ANSI/ISA-95.00.03-2013 Enterprise-Control System Integration - Part 3: Activity Models of Manufacturing Operations Management

 (Research Triangle Park, NC, 2013).
	7. ISA, 

ANSI/ISA-88.00.01-2010 Batch Control Part 1: Models and Terminology 

 When referring to this article, please cite it as J. Markarian, “Implementing Electronic Production Records,” 

Articles

Paperless operations improve efficiency and increase assurance of product quality.

Implementing Electronic Production Records

	Manufacturing execution systems (MES) automate production processes and, although often perceived as high-cost investments, can offer significant return on investment by improving efficiency and reducing errors. In addition, new web-based approaches to implementation promise to reduce cost and improve interoperability between different vendors’ systems. 

 interviewed three of the industry experts who presented at CBI's 10th annual conference, MES 2015, (Aug 12–13), about the benefits of implementing MES and their vision for the future of MES.

	Over the past 10–15 years, pharmaceutical and biopharmaceutical companies that have implemented MES have seen ongoing, quantifiable benefits from improved efficiency. One of the most significant benefits is the reduction of human error by, for example, automating data collection, entry, and reporting through use of electronic batch records (EBR) and electronic production records (EPR).

	"People make mistakes-often simple mistakes that are not caught by other people.  Our attention wanders, we lose focus, and we get distracted and forget important steps," notes Dennis Brandl, immediate-past chairman of the Manufacturing Enterprise Solutions Association (MESA) Americas board, president of BR&L Consulting, and keynote speaker at the MES conference. "By reducing the need for human input, providing auto-checking workflows, and letting the computer double-check work, productivity in the pharma industry has been continually improving. Companies that have implemented MES and other workflow automation systems have seen year-to-year productivity increases that don’t go away."

	In addition to automating mundane, manual data-collection tasks and getting more product through an existing manufacturing environment without increasing headcount, MES increase the efficiency of the product-release process, adds Keith Bowen, general manager of LZ Lifescience. Bowen gave a presentation at the MES conference on developing a business case for MES. "Following an automatic executing sequence for making a product, with the quality team working in parallel with the production team, leads to at least a 25% increase in productivity," explains Bowen. 

	A high level of automation is not required to achieve benefits, he says. "In a small pharma solid-dose plant that I visited recently, the per-year measurable benefit was half a million dollars, with an ROI of less than one year," he reports. A key to developing a business case is targeting measurable, objective savings and mapping these to MES product modules for specific products. It is important to use actual manufacturing activity data and to purchase only what is needed, Bowen says, because large MES modules may contain functionalities that aren’t required for a particular company's process.

	In addition to perceptions of high cost, another barrier to MES adoption in pharma has been lack of cross-vendor compatibility, says Brandl, "Workflows developed in one system cannot easily interact with workflows in other systems; data collected in one system is not easily shared with other systems. This means you have to pick one vendor and stick with them, even if they are only adequate, or even inadequate, in some areas."

	Brandl suggests that MES suppliers embrace the “app” model that uses independent internet application programs to share data from multiple vendors in one human-machine interface environment. A virtualized system on a smart phone or tablet would create a lower entry cost and enable more companies to use MES more fully. "Even with measurable economic advantages, companies are still reluctant to spend hundreds of thousands of dollars to implement MES," says Brandl. "With a lower entry cost...benefits can be applied to all areas of production, not just those with the biggest problems."

	Web-based MES products are already available, Bowen says. "Web-based MES products reduce the cost of MES solutions by hundreds of thousands of dollars and even more for large sites, and that is just on the hardware costs. The software sequences can be configured more quickly using a library of modules and operations which provide the building blocks for new-product master-batch records, resulting in a faster time to benefit from an MES solution."

	A long-term vision for MES in the pharmaceutical industry is to have "streamlined, efficient, out-of-the-box business process library templates for manufacturing facilities (of each type)," says Bowen. MES will allow the facility of the future to combine the best workflow practices of the past 20 years with new, more efficient, corporately controlled business processes, he notes.

	Analyst and advisory firm Axendia presented findings from a 

survey of the MES life-science community 

at the conference. The objective of the survey was to identify current issues and benefits, as well as requirements for next-generation MES.

	The survey found that many in industry view MES primarily as a tool to solve the problem of eliminating human error and ensuring that records are complete (i.e., regulatory compliance), notes Daniel R. Matlis, president of Axendia. "FDA wants industry to focus on quality rather than compliance, but two-thirds of brand owners surveyed identified ‘improved regulatory compliance’ as the main benefit when implementing MES, while only 44% see improving product quality as the top benefit. We would hope to see that product quality is the driver, and that compliance is the baseline and a direct side effect." Software vendors who answered the survey had yet another perspective, with 60% selecting a reduction in data entry errors and reducing manufacturing cycle time as the most important benefits of MES.

	The survey went on to show an even bigger disconnect between vendors and brand-owners regarding the top future requirements of MES. Most vendors (67%) chose "Internet of Things" as a top requirement, but brand-owners selected "global visibility," "predictive maintenance," and "manufacturing optimization."

	"This dichotomy is a concern because vendors may be building software to support an internet of things, but this may not be a fit for what industry says it needs," notes Matlis. "The ability of MES to support global visibility is key because industry is globalizing. Most MES today are designed for one plant, resulting in the need to aggregate data for multiple sites. To optimize capacity and improve product quality, however, decision makers need to be able to compare parameters at multiple sites to identify critical to quality attributes and prepare accurate forecasting."

	In addition to global visibility, next-generation MES should provide visibility across the entire supply chain. "Much of the metrics data that FDA is looking for in the new quality metrics initiative could come from MES. Visibility throughout the supply network is important, however, because the brand owner may need to report data from outsourced processes, not just the in-house manufacturing pieces," explains Matlis.

	Improved predictive maintenance is also part of optimizing manufacturing processes. "Software should provide tools that enable industry to become proactive and ultimately predictive of product quality, which ties in to operations, maintenance, and training," says Matlis.  

	These capabilities either don't currently exist in MES or are not user friendly, concludes Matlis. "It is important for vendors to support the needs of brand-owners and for both to look forward to ensure that the systems being implemented address the future needs of industry rather than merely fixing issues of the past." 

MES has already rewarded early adopters by reducing errors; next-generation technology will enable broader data analysis.

Proactive Optimization: the Future of Manufacturing Execution Systems

Shipping of pharmaceutical drug products­-which may involve long, complex routes and require temperature-controlled environments-can be challenging. "Temperature excursions, customs delays, packaging breakdowns, incorrect shipping, and packing choice are all risks inherent in today’s global logistics market," notes Sue Lee, global technical portfolio manager for World Courier. The shipping process is crucial; indeed, "Lives may depend on a drug making it safely from origin to destination, within temperature range, and on-time," notes Carl Asmus, vice-president of supply chain solutions and market development at FedEx.

 spoke with Lee; Asmus; Brian Kohr, president and CEO of CSafe, a cold-chain solutions provider; and Wanis Kabbaj, marketing director, UPS healthcare strategy, about these risks and the shipping solutions available to mitigate them.   

: What type of bio/pharmaceutical products are the most challenging to ship, and what solutions can be used?

: As the industry moves from ‘blockbuster’ products to personalized medicine, especially customized treatments for patients with rare diseases, expensive medications with low volume and high value will become the shipping norm. These shipments present extreme challenges in their intrinsic value. At the same time, we’ve seen a significant jump in the number of clinical trials conducted in emerging markets, where transport and storage of investigational medical products and patient samples can present a host of daily and diverse obstacles.

	Solutions for these shipments can be as unique as the shipments themselves. The expertise and control offered by a knowledgeable shipping partner-in everything from choosing the best system for the route and correct preconditioning of phase-change materials, to correctly configuring and positioning temperature monitors-are invaluable. The right packaging, following the right route, and the right expertise in each local market is crucial to providing a successful, unbroken supply chain for these potentially life-saving therapies.

	The recent partnership of World Courier with Medical Research Network (MRN) seeks to address many of the challenges of global clinical trials by creating a solution that combines product transport, storage, and nursing services in a secure, transparent solution. As emphasis shifts to patient-centric medicine, the question is not just getting a product from point A to point B, it’s also what happens to the product once it gets to point B.

	Lastly, new therapies are bringing a broad range of temperature needs to the supply chain. For example, there are now therapies that require storage at body temperature, and by necessity they will require a different approach compared to the traditional cold chain. Humidity, light, and even movement-sensitivity (i.e., products that cannot be jarred during shipment) might be factored into shipping concerns. All combined, it’s safe to say that as products themselves grow more complex, more diverse, and more specialized, supply-chain technologies and processes must become more advanced to support individual shipper needs.

: New, large-molecule, biologic treatments are increasing. These drugs are typically less stable than small-molecule drugs, making them more challenging to ship and requiring a highly customized solution. A high-end cold-chain solution using active containers and an extensive visibility control-tower solution is key.

	In addition, high-value drugs that are shipped in a small-package network require acute attention to detail. These shipments travel as one package among others, but because of their value we need to make sure they are shipped to the right person and on time. In this case, properly engineered passive packaging is key. Appropriate packaging combined with proactive monitoring and intervention adds layers of protection.

	Controlled substances like oxycodone present potential security risks and become challenging to ship. To mitigate these risks, we use real-time monitoring devices that track shipments constantly by using geo-fencing. Geo-fencing allows UPS to predetermine a safe route and define an acceptable digression distance for the drug to mitigate diversion and theft.

	Any biomaterial that requires cryogenic temperatures (-150 °C), such as clinical trials or biologic materials (e.g., blood, tissue, reproductive material), presents challenges within the supply chain. UPS works with a cryogenic container that is designed for our network and holds the temperature at -150 °C for at least 10 days. Visibility solutions help customers keep an eye on these shipments in real-time.

: Complex pharmaceutical trials offer many challenges, from security to temperature control. For example, FedEx recently worked with Clinical Supplies Management on a trial involving medication that was prepared in a laboratory, shipped overnight throughout the United States to be used within 48 hours, and maintained at 2-8 °C. Tracking and monitoring devices enabled verification of location and temperature control.

: What are the most concerning aspects of temperature control for the shipping service provider? For the customer?

 Challenges are similar for both a service provider and their customers: finding a solution that performs; meets regulatory obligations; meets any other objectives, such as sustainability; and has an acceptable cost.

: For the shipping service providers, there are three concerning aspects of temperature control: hand-offs, customs, and unexpected events. When a product is transported from origin to destination, the chain of custody can become complicated and long as the product passes among the shipper, the airline, the forwarder, and eventually to the end customer. All of these changes in custody are potential areas of concern as the risk for temperature deviation increases. As supply chains become longer and cross multiple borders, customs is a key area of concern for providers. Some countries outside of North America and Europe have much slower customs processes where goods may be held up in transit longer than expected. Finally, unexpected events, including mechanical issues as well as low probability, high-risk events, such as labor strikes, extreme weather, volcano eruptions, and earthquakes, can have strong consequences on the integrity of temperature-sensitive shipments. Providers must have a firm hold on the amount of risk they are willing to accept and contingency plans in place to react or mitigate any risk associated with unplanned events.

	For the customer, there are two main temperature-control concerns: cost and quality. Customers must find the right tradeoff between cost and the quality of their temperature integrity. At a high cost you can mitigate most risk, but is that something you want or need? How do you get to a point where the cost is competitive, but quality and risk mitigation are high? Contracting the right quality agreement with providers and ensuring it is respected throughout the entire supply chain is important. If the provider is using third-party vendors, how do you make sure that the service level you were sold is being taken into consideration at every step of the supply chain?  Outline the level of monitoring, auditing, and visibility that is expected and formalize an agreement to make sure it gets done.

: How do you address shipping requests to areas that do not have facilities for temperature control?

: Packaging and transportation solutions that can maintain temperature integrity and also eliminate unnecessary costs are key. For example, thermal blankets for pallets are available to offer protection against sunlight, humidity, and tarmac heat.

: Controlling the external temperature will always remain the best possible option, whether using temperature-control offerings from the airlines, certified airports, or over-packing the whole consignment with an active unit. However, these methods are not always a viable option due to lack of infrastructure at the destination. Manufacturers need to invest in packaging that is independent of the physical facilities available over the duration of the shipment, allowing the shipment temperature to remain stable even when storage conditions differ from expectation.

	It is important to have a knowledgeable team on the ground at every step. A reliable partner that can be present during pickup and delivery will allow for greater control over the product’s shipping life. All challenges and risks should be clearly identified in advance of the product being shipped, so that the shipping partner can work to alleviate issues early and often. This approach is also hard wired into regulatory requirements, including the European Union’s good distribution practice guidelines.

: Most of the global areas where UPS operates do not have temperature controls. A key way to address requests in these areas is through packaging and monitoring services. Cold-chain packaging will protect the product from temperature variations throughout the trip. Active, passive, and semi-active packaging solutions can be considered in conjunction with the known temperature conditions of the journey. Once proper packaging is defined, the compatible mode of transportation can be determined.

	Passive packaging may be protective for a certain amount of hours, so you must ensure a timely delivery before the pack-out expires. For active packaging, you need to make sure that the temperature is maintained throughout the supply chain, which can be done by implementing processes and training employees on how to handle those active-packaging solutions when they need to handle or intervene. Risk-management solutions must be in place for handling temperature-sensitive freight. A solution that proactively determines when a shipment is likely to be distressed or in jeopardy, an improved track-and-trace solution for real-time risk management, and capabilities to act on the data to expedite or reroute the shipment are all important components of a risk-management solution.

	It is important to note that the idea of temperature-controlled facilities providing full coverage throughout the supply chain is misleading. No full chain is completely temperature-controlled without appropriate packaging. When product in passive packaging leaves the controlled premise of a facility, truck, or airplane during handoff, it is in danger of temperature excursion if not delivered by the time the packaging expires.

When we designed our active packaging unit, we created a solution that did not require refrigerated trucking, refrigerated warehousing, re-icing or any other human intervention other than moving the product from A to Z. If there are no temperature-control facilities at Z and the container was going to sit for a period of time, the container is designed to simply plug into a wall outlet.

: Identifying and mitigating risk is crucial. Do some risks depend upon the mode of transportation, and what factors go into choosing transportation mode?

: Risk, particularly for temperature control, absolutely depends on the mode of transportation. Typically, the faster and more integrated the mode, the lower the risk. For example, if you ship a small package by air with an integrator like UPS you are only dealing with one vendor that controls all the assets and the network that your product is transiting through, and you are transporting the product quickly. In this instance the handoffs and exposure to the outside environment are limited, so there is lower risk.

	On the other hand, a ground transportation shipment over a long distance and through multiple transportation providers and modes (i.e., truck and rail) is subject to more risk. The mode is much slower than air and the exposure to external temperature variations increases during handoffs.

	Cost, temperature, and timing are all important in selecting the appropriate mode of transportation for a temperature-sensitive shipment. It is important for shippers to leverage extensive logistics portfolios with global air, ocean, and freight services. These should give customers the flexibility to meet specific cargo size and timing needs while maximizing routing, transit times, and cost management.

 Each mode of transportation (air, ocean, and ground) provides different benefits and risks. The risks include cost, likelihood of quality issues, liability, and level of capital deployed due to inventory in transit. Not every product or routing is suited for the same supply-chain solution or for every season. Companies that exercise and deploy various options are leading the way. Everyone wants simplicity, but simplicity may bring increased costs and increased risk. An active temperature-control container, for example, all but eliminates the human and environmental elements, but may not be the right supply-chain option from a cost perspective. There is always that crucial balance of cost versus risk.

: Transportation mode is only one element of the decision; it is important to determine the ideal transportation mode for their shipments based on many factors, such as service level and price point.

: As shipping and packing technology advances, the goal is to reduce the inherent risks associated with the mode of transportation. Experts agree the shipper should consider choosing packaging that is independent of the supply chain itself, which can keep shipments on-temperature. The question is less about mode of transport, and more about choosing the right packaging for your product and its journey. For example, semi-active packaging solutions usually bode well for shipments that are only going a short distance. However, for longer distances, customers should be looking at passive packaging solutions like phase-change material. Passive packaging allows for more precision and temperature control and maintains product stability over long distances and through extreme climates.

 When referring to this article, please cite it as J. Markarian, “Understanding Risks in Pharmaceutical Shipping,” 

Choosing the correct shipping solutions, including packaging, transportation mode, and monitoring, helps mitigate the risks inherent in global logistics.

Understanding Risks in Pharmaceutical Shipping

 surveys readers who work in finished drug manufacturing, both solid dosage and parenterals, to learn how well today’s equipment meets their needs. The survey also examines industry issues and trends. For 2015, themes included continuous manufacturing, process analytical technology (PAT), quality by design (QbD), and quality metrics (1).

	Results suggest that most professionals who operate, supervise, or engineer pharmaceutical manufacturing systems are satisfied with existing equipment and innovation. Responses suggest that more readers are using PAT, QbD, and continuous manufacturing, but that lack of knowledge may be limiting growth of these technologies.The following is a summary of findings from the 2015 survey.

	Respondents who use solid-dosage equipment indicated that they are, for the most part, satisfied with the equipment they are currently using. Ratings were similar to those given in 2014 (2). As shown in 

, in six categories (encapsulation, tablet compression, coating, packaging, mixing/blending, and granulation), nearly 90% or more said utility was excellent, and that they were completely satisfied or replied with “good, but see areas for improvement.”

	Approximately 80% of respondents indicated that powder transfer/materials handling and feeding/dispensing equipment were excellent or good. In-process testing/PAT and process control/automation, however, were indicated by one-third or more of respondents as “poor, needs significant improvement” or “inadequate, many problems.”

	Integration with manufacturing and business systems, which was a new category for 2015, also ranked relatively low. Innovation is generally keeping pace with needs in these areas, respondents said, although system integration stood out as a potential area for improvement, with 23% of respondents stating that solutions are not available for many issues.


	Just over half (53%) of the respondents who use solid-dosage equipment indicated that they employ continuous processing either overall or in select unit operations, which is an increase from the 40% who responded this way in 2014. The expectation for technological advances in continuous manufacturing is high. Approximately 27% believe that in the next five years, technology will evolve to permit end-to-end continuous manufacturing from raw materials to finished drug product without a break between API and drug product. In addition, 29% believe that technology will evolve to permit fully continuous manufacturing of solid-dosage drug products, with the conventional break between API and drug-product manufacturing, and industry will begin to use these processes. Approximately 30% believe technology will evolve to permit fully continuous manufacturing, but industry adoption will lag or use it in select unit operations.

	More than half of respondents said that capital costs and insufficient expertise were barriers to implementing continuous manufacturing at their facilities. In addition, 41% complained that the PAT solutions available in the market were not sufficient to enable continuous processing, citing that as a barrier, while 37% said that concerns about regulatory acceptance were impeding use of continuous manufacturing. Less than 30% of respondents thought there was a lack of equipment available in the market.


	Satisfaction with equipment used in parenteral manufacturing was high (see 

), and the percentages of respondents rating this equipment as “excellent” or “good” were generally similar to or higher than those in 2014 (2).

	Nearly all areas had satisfaction rates of approximately 80% or more.  One exception was that more than a quarter of respondents noted significant problems in integrating systems for existing equipment; 15% noted a need for more innovation in this area. Just over 10% of respondents noted a lack of innovation in process control and automation; in all other areas, more than 90% of respondents were satisfied with the level of innovation.  


	Of respondents in both solid-dosage and parenteral manufacturing who use containment for high-potency drug production, just over half indicated that their company’s level of activity (either in-house or outsourced) had increased in the past year. When asked to choose the one most challenging area for high-containment/high-potency, responses were diverse, as shown in 


	Keeping track of equipment problems and analyzing trends to improve operations are not new concepts in manufacturing. A pharmaceutical industry-wide metrics initiative, however, will soon be launched. Regulators, industry associations, and manufacturers have been collaborating to identify appropriate quality metrics, and FDA published draft guidance on July 29, 2015. The Quality Metrics Project Team of the International Society for Pharmaceutical Engineering (ISPE) concluded its initial pilot program (Wave 1) in April 2015, and in June announced  a second pilot program (Wave 2). These metrics will be used by regulators for risk-based plant inspections, but pharmaceutical manufacturers can also use them for continuous improvement. Nearly 90% of respondents to this year’s survey believe that metrics and trend analysis enhances the ability to improve equipment operation. Nearly three-quarters of respondents use trend analysis to evaluate equipment performance, and 65% have metrics in place to measure equipment failure.

	A little more than half of survey respondents, in both solid-dosage and parenteral equipment areas, were aware of equipment failures that had led to significant downtime or quality problems in the past year. These failures were attributed somewhat evenly to the following broad categories of root causes: contamination or cleaning (29%), utilities (28%), process validation (20%), and nonconformance (19%); other causes (4%) were mechanical issues with the equipment itself.


	In the four equipment areas surveyed (see 

), at least half of respondents apply QbD to some extent, and 20-30% fully use QbD (in process development/optimization). Some (16% in solid dosage, 22% in lyophilization, and 27% in sterile/aseptic processing) still do not use QbD. 

	Barriers to implementing or using QbD principles (multiple answers allowed) included lack of knowledge or training (53%), regulatory guidance clarity (50%), management buy-in (34%), and availability of necessary equipment/software tools (30%). Another barrier noted was the cost and time required. Approximately 10% say no barriers exist.

	PAT can include many types of tests to measure in-process materials. Availability of PAT has increased, although a lack of standard solutions and experience still hinders use (3). 

 shows the breakdown of PAT use by survey respondents in five manufacturing areas. In all areas, 25-33% of respondents use PAT, and another 26-44% plan to implement PAT use in the coming year.  Respondents indicated that the benefits and drivers for using PAT (multiple answers allowed) include better process understanding (44%), increased efficiency (40%), shorter process times (34%), and reduced costs (31%).


	When asked to identify the most important areas for innovation in pharmaceutical manufacturing, respondents noted a wide range of issues, including continuous manufacturing, single-use technologies, PAT, process control, and QbD. Others noted cost as an important issue, including making single-use and other new technologies more affordable, as well as lowering costs by reducing downtime and running processes more efficiently.

 Equipment and Manufacturing Survey targeted individuals in production and engineering. The survey was conducted by email in May and June 2015. Approximately 34% of respondents were from innovator pharmaceutical companies, 29% were from generic-drug companies, and 22% were from contract manufacturers. The remaining respondents (less than 6% each) included consumer healthcare companies making over-the-counter products, equipment or machinery vendors, excipient and raw material suppliers, and consultants. Respondents were split nearly evenly between solid-dosage and parenteral drug manufacturing. Companies represented by the survey manufacture products in diverse geographies. Respondents could choose more than one region, and they indicated production in: the US (61%), Canada (21%), Mexico/Central/South America (21%), Europe (51%), Asia (41%), and other regions (13%), which included Africa, Australia, India, Israel, and Russia.

 Equipment and Manufacturing Survey.
	2. J. Markarian, 

 When referring to this article, please cite it as J. Markarian, “Evaluating Package Integrity,” 

Taking the Pulse of Manufacturing Trends and Equipment Use

	Twin-screw extrusion, a continuous mixing process, is gaining acceptance for producing solid-dosage drugs as developers deepen their understanding of how the process can be applied in pharmaceutical manufacturing. One commercial use today employs the well-established extrusion of plastic parts (e.g., fiber, tubing, or rods) and blends in a drug to produce a combination drug–device product. Another application, often called hot-melt extrusion (HME), uses a twin-screw extruder to combine excipients with APIs to improve bioavailability or for controlled release or taste masking. In addition, an emerging use of the twin-screw extruder is as a continuous granulator, which is an alternative to a batch granulator for agglomerating and homogenizing particles to improve powder-compaction properties for tablet pressing. Over the past decade, much has been learned about optimizing equipment set up and processing conditions for these applications, and research continues to develop further understanding and promote use.


	Although twin-screw extruders have been used in the plastics industry for decades and are well understood, using the equipment for granulation is relatively new. However, "a broad scientific community is investigating the specific requirements of pharmaceutical applications and their implementation with twin-screw granulation. So the level of understanding is growing quite rapidly," notes Dirk Leister, technical marketing leader, material characterization products, Thermo Fisher Scientific. A powerful aspect of the twin-screw extruder is its modular design; screw segments can be combined in various shapes and orders on the screw shaft to make a unique design that has a significant effect on product quality. The segments include conveying elements for moving material; mixing elements for shearing, mixing, or dispersing; and distributive flow elements for distribution of small quantities of additives or shear-sensitive APIs, explained Leister in a webinar (1). Although most research to date has been based on specific formulations, "There is already momentum around gaining a more universal understanding of how conveying, mixing, and distribution screw elements are influencing the granule formation and quality," noted Leister in an interview with 

	Some general screw designs have been determined for granulation. For example, mixing zones in granulation tend to be shorter and less intense compared to those used in HME, and a compaction section at the end of the screw (close to the discharge) should be avoided, says Leister. In addition to screw design, important parameters that affect the level of fines and porosity in granulation include feed rate, liquid/solid ratio, and screw speed. Barrel set-up and total length of the barrel, which is the reaction chamber of the granulator, also have an impact on the process, says Leister.

	An advantage of a twin-screw granulator is that it is easy to control, and parameters can be changed without stopping the process, which aids performing a designed experiment to define a process window. "Parameters like overall torque, temperature along the barrel, screw speed, and feed-rate can be monitored and adjusted quickly and precisely, and the twin-screw granulator will return to steady-state quickly," says Leister.

	"Industry and academia are aggressively tackling issues related to commercialization of this process," added Michael Thompson, professor in the Chemical Engineering Department at McMaster University in Canada, in a presentation at the Leistritz Pharmaceutical Extrusion Seminar (2). Researchers have come a long way in characterizing the mechanisms occurring inside the extruder. "Screw design is the single most important factor in affecting the granulation process," said Thompson, who showed how placement and pitch of kneading blocks and conveying elements, as well as wetting methods, affect the granules. Twin-screw granulation has matured so that it can be used effectively to eliminate downstream milling, but researchers have not been able to eliminate downstream drying, concluded Thompson.

	A benefit of twin-screw granulation that is driving its use is its flexibility, comments Leister. As a continuous, time-based (rather than volume-based) process, twin-screw granulation can process small or large volumes of material as needed. Although existing batch granulation equipment for validated processes and products is not likely to see wide-scale replacement at this point with twin-screw granulation, manufacturers are considering the continuous process for new products, concludes Leister, "We expect a significant growth in commercial twin-screw granulator projects within the next 3-5 years."

Evaluating screw design for hot-melt extrusion


	Hot-melt extrusion uses the same basic extruder equipment as twin-screw granulation but with a different screw setup. Several presenters at the Leistritz Pharmaceutical Extrusion Seminar described the influence of screw design (i.e., the type and placement of different screw segments on the shaft) on the mixing process and the properties of the end product.  

	Researchers at the University of Maryland (UMD), led by David Bigio, associate professor in the Mechanical Engineering Department, have developed a new tool to further evaluate the effect of twin-screw extruder design on product properties. Although many models use residence time distribution (RTD) as a way to characterize the effect of mixing, the group's experiments show that RTD does not directly correlate to the stress the material experiences. They have developed an approach to create a residence stress distribution (RSD) as a function of operating conditions. The approach employs polymeric beads that rupture at a specific stress. The percent break-up of beads quantifies the amount of material that experiences that stress and has been shown to be a function of screw speed and specific throughput. Masters student Ben Dryer presented his work in developing an equation for percent break-up and relating it to the final product properties of degradation, bioavailability, and residual moisture.

	"A single, three-dimensional equation that better predicts material behavior in the extruder could be powerful for computer modeling and improved understanding of twin-screw extrusion for pharma as well as other applications," concluded Bigio in an interview with 


	Researchers from Merck; the Research Center for Pharmaceutical Engineering in Graz, Austria; and simulation software company ANSYS presented work to model a HME process using one- and three-dimensional commercial modeling software (4). Improvements in such models enable software to be used to evaluate screw design and process conditions 

	Barriers to use of HME have been limited laboratory-scale equipment capability and the fact that not all APIs- depending on physicochemical properties such as melting point and organic solubility-are suited to HME. As a result, most early formulation work has been performed with spray drying, said Jim DiNunzio, head of the HME Technology Development Team at Merck, in a presentation (5). Recent modeling work and an improved process understanding are being used, however, to identify optimal processing conditions and move formulations developed in spray drying to HME. "We are now able to link characteristics assessed at small-scale to interactions in the melt state influenced by processing parameters, which facilitates using HME earlier in the development process. Eventually we hope to use HME earlier in development by utilizing small-scale predictive technologies supplemented with modeling and simulation to extrapolate at-scale performance," explained DiNunzio in an interview with 

	1.     D. Leister, "A Modular Approach to Continuous Granulation," webinar (June 24, 2015).
	2.     M. Thompson, "Progress in Continuous Granulation by Twin Screw Extrusion," presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, June 18, 2015).
	3.     B. Dryer, et al. "Pharmaceutical Application of the Residence Stress Distribution," presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, June 18, 2015).
	4.     D. Johnson, et al., "Hot Melt Extrusion Modeling," presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, June 18, 2015).
	5.     J. DiNunzio, "Formulation and Process Design of Melt Extruded Dispersions," presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, June 18, 2015).

Improved characterization of twin-screw extrusion enables increasing use in pharmaceutical manufacturing.