	Continuous manufacturing of pharmaceuticals could reduce the inefficiencies found in batch manufacturing. It creates an opportunity to implement more modernized manufacturing processes, which lead to better quality end products. This technology could also help prevent drug shortages through faster and more responsive supply chains. Continuous technologies offer the potential to replace the outdated "quality by testing" regime currently employed by the industry with a more robust "quality by design" system, which is possible because of the improved process understanding and  robust control strategies gained through continuous processing, said Bayan Takizawa, co-founder and chief business officer at CONTINUUS Pharmaceuticals, at a conference session on continuous manufacturing at INTERPHEX on March 21, 2017. Industry, academia, and regulators have spent significant time and money over the past decade to develop pharmaceutical continuous manufacturing for solid-dosage drugs, and commercial approvals-such as Janssen and Vertex for drug products and Lilly, GSK, and Lonza for APIs-have been the fruit of this labor.

	Although these processes have adopted continuous unit operations, overcoming the disconnect between drug substance and drug product and moving to an end-to-end continuous system could produce even greater rewards, suggested Takizawa. Both CONTINUUS and Novartis are both working on end-to-end systems launched from work at the Massachusetts Institute of Technology (MIT). Novel process technologies and an integrated, system-wide approach may eliminate the “corrective steps” (i.e., granulation, compression, blending, milling) necessitated by existing processes, he explained; development continues in this area.     


	An ongoing challenge for continuous processing is integrating unit operation equipment and control systems. More integrated systems are becoming available, however, noted Doug Hausner, associate director at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), at the INTERPHEX session.

	One example is a consortium including GEA, G-CON, and Pfizer that developed the Portable, Continuous, Miniature, and Modular (PCMM) solid-dosage system; GSK joined the consortium in 2015. Pfizer’s prototype PCMM won the International Society for Pharmaceutical Engineering (ISPE) Facility of the Year Awards (FOYA) for the 2016 Equipment Innovation category, and GEA’s ConsiGma continuous system won an Excellence in Pharma award at CPhI 2016. 

	At L.B. Bohle’s Technology Center in Ennigerloh, Germany, customers can test products on a continuous processing system that includes blending, dosing, tableting, and coating; process analytical technology; and an integrated control system.  The modular system allows wet granulation, roller compaction, or direct compression, explained company representatives at the INTERPHEX exhibit.

	Glatt’s continuous solid-dosage processing systems are operating at its Innovation Center in Binzen, Germany, which was inaugurated in November 2016. The system can use direct compression, mid-shear wet granulation (in a blender), or high-shear wet granulation (in a twin-screw extruder); the company is also working to integrate its fluid-bed spray granulation into the continuous system, explained Ed Godek, manager of process technology in the Glatt Equipment and Engineering Division, at INTERPHEX. Glatt has been developing the wet granulation continuous system with Thermo Fisher Scientific’s Pharma 11 twin-screw extruder for the granulation step and Innopharma’s Eyecon process analytical technology (PAT) tools. Eyecon measures particle size at the outlet of the wet-granulation process as part of a feedback control loop that keeps particle size within specification and also after the dryer. Process control for the system was done in-house by Glatt.

	Integrating process control is an important, but complex, piece of continuous processing technology. Process control system experts should be involved as early in the development process as possible, suggested Pamela Bruen Docherty, Life Sciences Industry manager USA, at Siemens, in a presentation at INTERPHEX. Model-predictive control handles multiple inputs and outputs and is needed for the advanced process control that connects the pieces of a continuous system, she explained. Many advances in system control and process modeling, in both solid-dosage and biopharmaceuticals, have been achieved in the past several years.


	Many companies have developed the required technical capabilities and are poised to implement them, but seem to be in a “wait and see” mode, commented Hausner at the INTERPHEX conference session. Most of the technical barriers have been overcome by the industry as a whole, he noted, but having the right people, knowledge, and equipment at an individual company can be a challenge. A “big picture” mindset, rather than evaluating the advantage of the new technology on a product-by-product basis, is needed to promote high-level support for capital expenditures, said Hausner. The perception of regulatory uncertainty, particularly in large, important markets, such as Europe, is another limiting factor.  


	FDA has been quite clear on its support of continuous manufacturing over the past several years. FDA’s message has been consistent that it sees no regulatory hurdles for implementing continuous manufacturing, it supports the implementation of continuous manufacturing using a science- and risk-based approach, and it sees continuous manufacturing as consistent with FDA’s quality initiatives (1,2).

	Other regulatory bodies have perhaps not been as vocal in their support of continuous manufacturing as FDA has been, but the European Medicines Agency (EMA) has begun to express support and recently clarified its position, providing further technical specificity. At the 3

 FDA/PQRI Conference on Advancing Product Quality (March 22­–24, 2017), EMA’s Dolores Hernan noted that the current regulatory framework allows continuous manufacturing, and although specific guidelines are not available, the existing ones are supportive of this approach (3).

	Both FDA and EMA recommend communicating with the agencies early in development (2,3). “The toolbox is out there, and EMA and FDA want you to come talk with them to show them you understand these new tools as you go to use them,” notes Hausner.


	Several conferences in 2016, such as the International Society for Pharmaceutical Engineering (ISPE)’s 

, the FDA-American Institute of Chemical Engineers (AIChE) 

Workshop on Adopting Continuous Manufacturing

 International Symposium on Continuous Manufacturing of Pharmaceuticals

 organized by the Massachusetts Institute of Technology (MIT) and the Continuous Manufacturing and Crystallization Consortium (CMAC), have worked to increase understanding and to promote adoption of continuous manufacturing.

	In May 2017, the global International Institute for Advanced Pharmaceutical Manufacturing (I2APM) is hosting the 

Emerging Pharmaceutical Manufacturing Summit

, May 8–9, 2017 in Malta, to bring together first- and second-wave technology adopters, regulators, and academics. C-SOPS, one of the founding groups of I2APM and one of the event organizers, hopes that European regulators, in particular, will benefit from seeing the examples of commercially approved implementations of continuous manufacturing.

	The United States Pharmacopeial Convention (USP), in collaboration with C-SOPS, hosted a workshop in the US in 2016 on continuous manufacturing, one of the outcomes of which was a new expert panel that is now working to standardize terms and characterize materials specific to what it is calling PCM [pharmaceutical continuous manufacturing]. USP and C-SOPS signed a memorandum of understanding in February 2017 as part of their commitment to collaborate and work to make PCM more widely available (4). USP is hosting a 

on May 16–17, 2017 to introduce PCM to Indian pharma companies, particularly generic drug companies.

FDA Perspective on Continuous Manufacturing

,” Presentation at IFPAC Annual Meeting (Baltimore, Jan. 2012).	

Continuous manufacturing: Challenges and opportunities. EMA perspective

 FDA 3rd FDA/PQRI Conference on Advancing Product Quality 22-24 March 2017. 	

		USP, “Exploring Continuous Manufacturing Technology and Applications in the Pharmaceutical Industry,” (March 13, 2017), 

http://qualitymatters.usp.org/exploring-continuous-manufacturing-technology-and-applications-pharmaceutical-industry

” Presentation at MIT-CMAC ISCMP (Cambridge, MA, May 20, 2014). 

Articles

Feature

Although technical paths for continuous solid-dosage manufacturing have been laid out and equipment and control systems have been developed, industry is slow to move forward.

Paving the Way for Continuous Manufacturing

	Although the Drug Supply Chain Security Act (DSCSA) doesn’t require aggregation this year, “90% of the generics market wants to aggregate at least to the case, if not the pallet level,” Christopher Mueller, project engineer at Mettler-Toledo Vision Inspection PCE, told 

 in an interview at INTERPHEX 2017. “They want the supply chain advantages aggregation brings,” he explained. Having data about where product ultimately meets patient helps determine if marketing efforts are successful and helps combat counterfeiting and diversion. At INTERPHEX 2017 (Mar. 21­–23, New York), several exhibitors focused on helping pharmaceutical manufacturers comply with upcoming serialization DSCSA deadlines.


	Optel Vision and Adents chose INTERPHEX for major product launches. Adents introduced Adents Prodigi enterprise-level serialization and traceability software (see 

). Based on Microsoft Azure Cloud technology and supported by tools such as OEE Tracker and Supplier Portal from Supply Chain Wizard, the software not only helps firms comply with regulatory requirements, but also organizes serialization data to provide useful business intelligence. The Adents Prodigi software securely generates or imports serial numbers in accordance with regulatory requirements, collects serialization data, manages data transfer between sites, and provides a simple interface between trading partners.

Optel Vision presented its new Fast Series preconfigured products for serialization and aggregation. With a delivery turnaround as short as six weeks, the Fast Series provides options for manual, semiautomatic, and fully automated lines. Options include a compact Manual Print Station, which prints and inspects serialized labels and can serve multiple packaging lines; the PackStation FMP manual packing station; the PackStation SAP semiautomatic packing station; the portable Offline LabelTracker for label inspection, verification, and commissioning; and the CLTracker TE automated carton label serialization unit. Designed to be integrated on carton labelers, the CLTracker TE unit also imparts tamper-evident protection. Fast Series installations encompass hardware as well as software, installation and operational qualification documentation, operator manual, and integration and on-site training services.

	Another standardized serialization solution ready for quick delivery, the Antares Vision Quick Compliance Program from Antares Vision also supplies hardware, software, documentation, and services. Ready-to-ship modules include the Reel 2 Reel off-line label printing station, a manual packing station, and the Print & Check EVO Ready carton serialization system. The latter prints and checks serialized codes on carton flaps at speeds up to 300 units per minute.

	Mettler Toledo offers a standalone carton serialization station as well as kits to retrofit existing labelers and cartoners for serialization. As cases are filled, onboard software compares the serialized code on each carton and cross references it with the database to verify the number is valid and commissioned. When the final layer is complete, the system confirms the case is full and prints a global trade item number (GTIN) label for the case. Labels for partial cases are printed with a serial shipping container code. A similar process is followed to build pallets. Scanning a pallet label reveals the codes of all cases on the pallet, as well as the cartons in each case, so shipments can be checked without depalletizing or opening boxes.

	Another system that supports aggregation, the Navstar from ACG North America, provides 360-degree inspection of 2D codes. A cantilever design simplifies integration on bottling lines. A single dial adjustment provides easy and reproducible positioning of the system’s six cameras.


	Coding systems support serialization efforts. DPSS Lasers showed the Samurai ultraviolet laser coding system marking bottle bottoms with up to four lines of text or bar code. Mounted below the conveyor, the coder produces a permanent mark, without ink, debris or fumes, at rates up to 300 containers per minute.

	Another ultraviolet laser coder, the 7810 model from Videojet Technologies, is designed especially for marking high-density polyethylene (HDPE) bottles. The system can generate print as small as 4-point. Videojet also showed its 3340 Pharmaline carbon dioxide laser coding system. It prints up to four lines of text and barcodes (2D and linear) and offers processing speeds capable of generating serialized codes. A 600-mm marking window makes it possible for one coder to handle what previously required two units. Three wave lengths and different power settings and focal distances enable coding on labels, cartons, and virtually any packaging substrate except HDPE.

Exhibitors focused on helping pharmaceutical manufacturers comply with upcoming DSCSA serialization deadlines.

Equipment and Systems for Serialization Displayed at INTERPHEX 2017

	Single-use tubing can be used for the length of a biopharmaceutical product campaign and changed when a new product is to be manufactured. To prevent failure during lengthy use, tube life should be monitored and a preventive maintenance program enacted. 

 spoke with Gregg E. Johnson, global senior product manager for the Cole-Parmer peristaltic pump product lines, about these concerns.

 How long does single-use tubing typically last?

The lifespan for tubing is dependent upon pumping conditions- speed, pressure, fluid, and fluid temperature. Some new biopharm formulations of silicone tubing can last 200 to more than 1000 hours. For the Pharmed materials (made from a thermoplastic elastomer), life expectancy can be several thousands of hours.

 How does a company go about monitoring the tube life?

 In our testing lab, we monitor the tube life by recording the hours between failure. Once we have a pattern, we can set up preventative maintenance based on the specific installation. Each one is different due to different fluid, piping systems, and other devices in the fluid path.

 What are some rules of thumb for performing preventive maintenance?

 Preventative maintenance (PM) and the frequency at which it is performed is determined by the pump operator. A simple recommendation is to review the tube-life data provided by the pump manufacturer. A good place to start may be at 75 to 80% of the manufacturer’s data until a reliable pattern is defined. Each installation is different. Once this pattern is established, and longer PM cycles are desired, the operator can elect to extend the cycles to fit needs.

 How can tube life be extended by moving the tubing to a new position?

 If an operator is performing a long-term campaign and is concerned about tube life, he or she can extend the run and prevent the possibility of tubing failure by moving the tubing to a new position. This is accomplished by setting the system up with excess tubing on the discharge (outlet) of the pump. Once the campaign is running, the operator can, on a periodic basis-once a week or once a month-pause the pump rotation, open the pump head, and slide a section of unused tubing (from the excess at the start of the campaign) and move the used section from the pump head to the suction (inlet) side. The pump is then closed and restarted.

To prevent failure during lengthy use, tube life should be monitored and a preventive maintenance program enacted.

Equipment and Processing Report-04-19-2017

Paving the Way for Continuous Manufacturing

Equipment and Systems for Serialization Displayed at INTERPHEX 2017

Preventive Maintenance of Single-Use Tubing for Peristaltic Pumps