For the past few years, it has been no secret that many small to mid-sized pharmaceutical companies in the United States, the European Union, and beyond have not yet begun to prepare for serialization deadlines set by the US Drug Supply Chain Security Act (DSCSA), the EU False Medications Directive (FMD), and other traceability directives around the world (1).

	In the US, this compliance gap led FDA to postpone by one year the implementation deadline, moving it to November 2018 (2). The FMD’s deadline still stands at February 2019. 

	However, in the second quarter of 2018, Tracelink’s 2018 Drug Supply, Safety, and Traceability Report found that only one-third of 660 pharmaceutical manufacturers, contract manufacturing organizations (CMOs), wholesale distributors, hospitals, and pharmacies were confident that they were ready to meet requirements, and only half had prepared their internal packaging lines of serialization or projected the number of units that would need to be serialized each year.  The survey found that, at that time, only 8% of pharmaceutical manufacturers had integrated serialization processes with their CMOs and only 11% said their CMOs were ready to ship serialized product (3). Where executives from half of CMOs in the US felt ready, only a third of their counterparts in Europe did.

	Manufacturers and CMOs in Europe are well behind schedule, according to recent reports (4). Second quarter 2018 data from the European Medicines Verification Organization (EMVO) suggested that 50% of countries whose manufacturers sell pharmaceuticals in the EU will be too late to meet the FMD deadline. Even for all European suppliers to comply would require equipping some 10,000 packaging lines at 1500 pharmaceutical sites in a matter of months (5). Getting EMVO approval is itself a process that can take several weeks. First, a series of transactions must be submitted and reviewed before the company is allowed to submit relevant production and other data to the EU Hub.

	At the Serialization Innovation Summit, held on June 20, 2018 in Philadelphia and sponsored by the serialization IT supplier Adents, Maarten Van Baelen, market access director for Medicines for Europe, a generic-drug trade association, revealed the scope of the challenge. As of May 2018, he said, out of the 2200 pharmaceutical companies that will need to submit serialization data to EMVO for FMD, only 749 had done so. Meanwhile, further along the supply chain, only 10% of wholesalers were connected to the EMVO system, although they were working very hard to solve the “considerable technical challenges” involved, he told attendees at the June Summit.

	Solution providers have responded to these issues with a number of “quick compliance” tools-modular, template-driven approaches designed to help companies meet serialization requirements quickly. In May 2018, TraceLink, a cloud-based IT serialization solutions provider, introduced the EU FMD Express platform, designed to help smaller manufacturers and CMOs in Europe meet requirements and send serialization data to EMVO (6).

	As of June 2018, TraceLink reported that 34 companies had completed conformance testing using TraceLink’s kit. Of these, 11 companies received EMVO approval to submit data to the EU Hub and 14 companies were awaiting review. Biosyn is one company that reported good results from the program, while, in June, IBI Lorenizini, an Italian CMO and supplier, signed up.

	Adents, another cloud-based IT vendor, is approaching the serialization readiness gap with programs of its own. Started up in 2007 in France by specialists with experience handling provenance and serialization issues in the fine perfumes and champagne markets, the company introduced Serisa, a line-level serialization solution supported by Siemens, in 2010. In 2014, Adents released Prodigi, a cloud-based system designed to facilitate serialization data exchange. 

	In 2017, the company established a collaboration with Microsoft, and the two partners introduced NovaTrack to the US market in June 2018 (7). The approach, utilizing Microsoft’s Azure Cloud technology, is designed to incorporate blockchain and artificial intelligence, and to bring Internet of Things (IoT) technology to bear on cold-chain and other supply chain issues. Julien Faury, vice-president of operations for Adents Americas, says that the program features open architecture and works both at the centralized IT level and at the line level, using a “top down” approach and a cloud-native, vendor agnostic approach. 

	The company offers users a certified gateway to enable faster transmission of data to EMVS. It has integrated with the Origin database in the US, operated by the Healthcare Distributors Association, and is developing a gateway to Russia’s serialization database.

	The company is working with Microsoft to develop and optimize blockchain solutions using Microsoft’s Cocoframework, which offers 20,000–50,000 transactions per second. This speed is considerably faster than solutions based on Ethereum, according to Tianna Umann, cross-domain solution architect with Microsoft, who spoke at the June summit. 

	Both partners have assembled an industry workgroup lead by the Healthcare Distributors Association to evaluate different approaches to blockchain.  In addition, Adents and Microsoft are working on systems that would use Microsoft’s Hololens technology to train operators on serialization and make relevant documents accessible to them in their workspace via a wearable device. Hololens is based on the concept of Mixed Reality, which incorporates some of the digital elements of virtual reality, but operates in real space (8). Adents’ operations manager, William Minaeff, senior project director, shared some insights into pharmaceutical serialization with 

: What changes have you seen in the industry’s approach to serialization in 2018, as the DSCSA and FMD deadlines draw near? 

: We have seen several changes since FDA offered a year-long extension in 2017. FDA recognized that solution providers were finding it difficult to scale up to service the number of production lines required by the various pharmaceutical companies. As a result, many serialization service providers have had to hire hundreds of employees in a short time frame to meet demand. 

	The major hubs in the United States are in the San Francisco Bay Area, the Northeast, and of course, Research Triangle Park. Additionally, we see a large opportunity for external manufacturing in the Midwestern US. The beauty of cloud solutions is that they have unlimited scalability, so we are able to work with companies of all sizes and customize our solutions according to the size of the business. Further, Colombia and Brazil are emerging markets, while Canada will adopt serialization within the next five years due to changes in regulations. 

: Just a few months ago, many small to mid-sized manufacturers and CMOs had not even started formal serialization programs. Where are you seeing the greatest challenges?

: Serialization implementation faces the following challenges:

		Collaboration between thousands of parties

		Management’s view that serialization is a cost, not a benefit

		The need to share billions of terabytes of data.

: There are already a number of cloud-based data management systems available for serialization.  How is Adents’ different?

: Adents was established to explore the new generation of serialization software. The major challenge with serialization is not the actual marking or reading of serial numbers but rather the data management expertise that backs up the serialization. Over the past few years, Adents has created a new software suite, with an open architecture. 

	The first part of this software was released in 2010. This software-driven serialization solution took off very quickly in the European market. The solution is not only used in the pharmaceutical sector but also in the wine and spirits, and health and beauty sectors. 

	In 2012, pharmaceutical companies in the United States and Europe started to implement these processes and began to look into cloud-level solutions. Adents partnered with Microsoft in 2014 to codevelop Adents Prodigi, which was released in 2017. Adents has since grown to nearly 100 employees and more than half of its customer base consists of life-science companies. 

: What is needed to help more companies leverage the work that they have done to enable serialization to achieve broader business benefits?  

: As a serialization project progresses, there are many challenges that need to be faced and many sources of complexity. Serialization failures most frequently come from a failure to understand the scope of a serialization project, for example, failing to identify all stakeholders and their requirements (e.g., packaging, label change, supply chain, IT, and Enterprise Resource Planning [ERP]).

	Essentially, five key elements are required for a successful track-and-trace serialization solution for the pharmaceutical sector:

		Configurability, so that no specific software development is needed, in a platform that can be easily updated and upgraded, reducing human error.

		Scalability, so that after initial rollout, additional lines can be deployed seamlessly without having to duplicate the entire process.

		Interoperability (i.e., increased flexibility) so that users can choose the hardware that fits the best with their objectives, use existing equipment when possible, and minimize costs and delays in delivery.

		Site-level management capabilities to cope with change management. One centralized point from which configuration and processes can be managed can help to facilitate configuration management, data exchange, reporting, change management, and validation support as well as IT governance. Site-level management capability minimizes risks and help users prepare for future track-and-trace challenges.

: How is the industry moving beyond serialization to the larger goal of traceability?  

: Modern software companies rarely look past three-to-five-year planning cycles, due to the rapid change of technology and business requirements. However, if we look at the current pace of change in automation, robotics, regulatory requirements, consumer demands (from both customers and manufacturers), we begin to see the increasing role that software must play in manufacturing, to provide lifecycle management and support ‘right first time’ production goals.

Pharma Serialization Nears a Tipping Point

,” pharmtech.com, January 2, 2018
	2. PharmTech Editors, “

FDA Pushes DSCSA Serialization Enforcement Deadline Back to 2018

,” pharmtech.com, July 5, 2017
	3. A. Shanley, “

,” pharmtech.com,  April 5, 2018.  
	4. S. Milmo, “

,” pharmtech.com, June 1, 2018. 
	5. Press Release, “

TraceLink Customers Receive EMVO Approval for Data Submission to the EU Hub

Concern Voiced About Pharma’s Serialization Readiness

,” April 12, 2018, pharmalogisticsiq.com
	7. Press Release, “

Adents and Microsoft Introduce Blockchain Serialization Solution

Serialization Innovation: Latest Technologies for the Pharmaceutical Industry

	When referring to this article, please cite it as A. Shanley, “Serialization: Scaling Down for the Final Stretch" 

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Vendors are offering template-based models and direct data-filing services to help smaller companies meet imminent deadlines.

Serialization: Scaling Down for the Final Stretch

	Twin-screw extruders, which have found commercial use in making amorphous solid-dispersions for improving drug solubility and in loading drugs into polymers that can be shaped into drug-delivery devices (i.e., via hot-melt extrusion), are also emerging as equipment for continuous wet granulation, as well as for continuous mixing of wet gelatin mass for soft-gel capsules. 

	The ongoing development and commercialization of continuous manufacturing for oral solid-dosage (OSD) pharmaceuticals is creating a growing opportunity for continuous granulation processes, and twin-screw granulation (TSG) is already being used in commercial continuous manufacturing. Some continuous systems, such as GEA’s ConsiGma and Glatt’s MODCON, for example, use TSG. Twin-screw extruders are available in models designed for pharma processing from manufacturers including Coperion, CW Brabender, Leistritz, Steer, Thermo Fisher Scientific, and others.

	A twin-screw extruder has a modular design, and different types of screw elements can be arranged on the screw shaft to optimize mixing and to allow ingredients to be added to the machine at multiple locations (i.e., part-way through mixing). The same machine can be used for wet granulation as for hot-melt extrusion, but the hot-melt extrusion process requires external barrel heating to raise the temperature above the melting point (or glass transition temperature) of the polymeric excipient, while granulation takes place at lower temperatures, below the excipients’ melting point or glass transition temperature. 

	The primary benefit of TSG is that the extruders are intended for continuous manufacturing, notes Dirk Leister, technical marketing manager, process and pharma extruders for Thermo Fisher Scientific. “Extruders are time-based production-the same equipment can be used for different amounts of material. One can potentially use the same extruder for R&D as for production, by simply running longer. Or, the process can be scaled up to a larger extruder for higher throughput.” Thermo Fisher’s Pharma 11 (11-mm diameter) and Pharma 16 (16-mm diameter) twin-screw extruders are designed for both R&D and production. These extruders can be set up for both granulation and hot-melt extrusion, using conversion kits for the necessary hardware modification. Thermo Fisher recently introduced the Thermo Scientific Pharma 24 TSG, a 24-mm diameter twin-screw extruder dedicated for twin-screw granulation with a throughput rate of up to 70 kg/h. The extruder can be either integrated into a continuous production line or used as a standalone instrument for project development or small-scale production using either wet or dry granulation (1). The extruder has a 40:1 ratio of length to diameter that offers flexible adaptation for processing length, screw setup, and introduction of ingredients into the process. Minimal downtime is needed for cleaning, and online monitoring facilitates detection and segregation of out-of-specification product.

	In addition to flexibility of scale, continuous processes offer the potential for improved process control compared to batch processes and for on-line, real-time monitoring. The twin-screw extruder is considered a small-volume continuous mixer, and it creates a more uniform mixing history for more homogeneous distribution of drug, excipient, and binder (2).

	“Consistency is a big advantage,” notes Michael Thompson, professor in the department of Chemical Engineering at McMaster University in Ontario, Canada. “TSG can reduce lot-to-lot variation of the granulated product and reduces reliance on a specific seasoned operator in order to get the correct product quality by knowing when to stop the batch mixer.” TSG may need less binder or less water to produce equivalent granules to batch systems, which could reduce production cost. 

	How the primary variables in the TSG process affect product properties is relatively well understood at this point, although each formulation would need to be optimized. “Just about any formulation based on known pharmaceutical ingredients can be made into granules so long as the formulator has a working knowledge of the different techniques to ‘wet out’ the powders,” says Thompson. “I would always recommend to a company to study the binder-to-powder needs in each new formulation as if starting from scratch, but the initial machine setup and operating conditions can be treated as relatively generic.” Scaling up from a small laboratory machine to larger production equipment poses more challenges, however. “One can’t truly know a process until it has run for several hours, with the machine heated up by mechanical rotation and the feeders having gone through several fill cycles to fully learn the bulk density of the process’s ingredients,” cautions Thompson. “A product made from a 20-minute lab trial doesn’t necessarily translate to a continuously operated production process.”  

	Process analytical technology (PAT) is a crucial part of understanding and controlling a continuous process, and in-line measurements are used in advanced process control strategies and in quality-by-design studies. Innopharma Technology’s Eyecon

, for example, is a direct optical imaging system that captures images of the granule particles and analyzes them in real-time. “In continuous processing, the particle analyzer can be used to monitor particle size after a twin-screw, a continuous drier, or a mill, says Chris O’Callaghan, senior product manager at Innopharma.”

	In a continuous system, data are needed for both feed-forward and feed-back control to maintain key parameters and attributes as close to an ideal setpoint as possible, despite some variation in the inputs and outputs of each process stage. “While feed-back control is critical in ensuring that deviations do not continue to grow unchecked, feed-forward control can enable compensation of upstream variations in subsequent processing steps to ensure that variations introduced in early stages can be partially or fully corrected in the final output material,” explains O’Callaghan.

	“By measuring particles after granulation, deviations in the measured size can be used to alter parameters of the twin-screw (e.g., liquid addition and screw speed) to correct for the variation in particle size, while the speed of a downstream milling step may be temporarily increased or decreased to more finely or coarsely mill the granulate currently entering, thereby maintaining a more consistent output particle size.”

	More work is needed to further develop different types of PAT for TSG, says Thompson. In the McMaster University laboratory, researchers are looking at ultrasonic acoustic sensors to see what information about properties exiting the twin-screw granulator, such as granule size and moisture content, can be measured. Eventually, the researchers hope to also identify technology that can monitor incoming powders, which can also have a significant effect on end properties. For example, the size of a binder particle is known to affect granule size in hot-melt granulation, but a supplier of binder material might not measure or report binder particle size or changes in grinding because they wouldn’t affect chemical properties, notes Thompson. It would be difficult to track a problem with off-spec granules back to the feed materials, and a formulator might mistakenly assume something inside the extruder had gone wrong. 

	Sensors that are already built into extruders can also be used as PAT signals. The torque of the extruder drive motor, for example, should stay constant duringsteady-state processing, and can be used in process control, notes Leister. 

	Twin-screw extruders can also be used for continuous processing of gel mass used in casings for soft-gel capsules. In April 2018, Leistritz introduced a twin-screw extrusion (TSE) system to continuously mix and condition gel-mass formulations. The system, which uses a ZSE-LS model twin screw extruder, replaces batch mixing for gel-mass R&D and production processes, and the continuous process is inherently more consistent and repeatable, says the company. Continuous, real-time monitoring of the TSE process parameters ensures product quality.

	“The short residence time inherent with the TSE process section helps avoid degradation of the gel-mass,” explained Leistritz (3). “It is estimated that the residence time in the TSE process section is less than two to three minutes. … Raw ingredients (gelatin, starches, water, plasticizer, and other additives, such as colorants and flavors) are sequentially metered into the extruder process section where they are heated, hydrated, mixed, and pumped to an intermediate filling station.  The intermediate filling station refills two spreader boxes to form thin webs on chilled rolls, which are integrated with die rollers and liquid injection apparatus to produce soft-gel capsules.”  

	The food and polymer industries successfully transitioned from batch to continuous processing using twin-screw extruders fifty years ago, and use of TSG is expected to continue to evolve in the pharma industry, say experts (2). 

	1.    Thermo Scientific, “New Twin-screw Granulator Helps Maximize Throughput in Continuous Drug Manufacturing,” Press Release, June 25, 2018.

	2.    N. Kittikunakorn, et al., “Processes, Chllenges, and the Future of Twin-Screw Granulation for Manufacturing Oral Tablets and Capsules,” AAPS News Magazine, March 2018.

	3.    Leistritz, “Leistritz Introduces a Continuous Twin Screw Extrusion System That Replaces Batch Mixing for Gel Mass R&D and Production,” Press Release, April 16, 2018.

A twin-screw extruder can be used as a continuous wet granulator or as a continuous mixer for a wet gelatin mass. 

Equipment and Processing Report-08-15-2018

Serialization: Scaling Down for the Final Stretch

Considering Twin-Screw Extruders for Continuous Mixing and Granulation