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Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.
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.
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 Continuous technologies offer the potential to replace the outdated "quality by testing" regime currently employed by the industry with a more robust "quality by design" system, which is possible because of the improved process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.
Wait and see
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.
Regulatory agencies offer support
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 3rd 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.
Focused conferences spread the word
Several conferences in 2016, such as the International Society for Pharmaceutical Engineering (ISPE)’s Continuous Manufacturing Conference, the FDA-American Institute of Chemical Engineers (AIChE) Workshop on Adopting Continuous Manufacturing, and the 2nd 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 workshop in India on May 16–17, 2017 to introduce PCM to Indian pharma companies, particularly generic drug companies.
” Presentation at MIT-CMAC ISCMP (Cambridge, MA, May 20, 2014).