Continuous Solid-Dosage Manufacturing Platform Nears Prototype Installation

Experts predict an eventual shift from batch to continuous manufacturing processes. Regulators have expressed support for continuous manufacturing, which is a crucial piece for any pharmaceutical effort. Analytical and manufacturing equipment and control systems have been developed to fit the needs of continuous production, and companies are moving forward. In September 2013, GEA Pharma Systems and G-CON Manufacturing announced a manufacturing collaboration with Pfizer to develop a PCMM (portable, continuous, miniature, and modular) system to create a compact and mobile manufacturing platform for oral solid-dosage (OSD) drugs. The PCMM prototype integrates GEA’s ConsiGma continuous manufacturing platform and MODUL P rotary tablet press, in a 36-ft. wide G-CON autonomous GMP cleanroom structure called a megaPOD. The prefabricated process skid and POD form an environmentally isolated facility that can be installed in standard warehouse space. Maik Jornitz, president of G-CON Manufacturing; Richard Steiner, business development manager for ConsiGma at GEA Pharma Systems; and Michael O’Brien, head of Pharmaceutical Sciences Technology & Innovation at Pfizer spoke with Pharmaceutical Technology about the project.

Project statusPharmTech: What is the status of the PCMM project?

Steiner (GEA): At the moment, we are working on finishing the industrial skid. The collaboration is more than just a project on paper, we’re creating a tangible process solution that will soon be manufacturing real product. Right now, we’re in the factory acceptance testing phase for the equipment, which is almost finished. Soon the equipment will be combined with the G-CON megaPOD, finally bringing the project from concept to reality.

O’Brien (Pfizer): We are hoping to begin assembly early in the first quarter of 2015 in a Pfizer Groton (Connecticut, US) warehouse. The following are some of the principles that will be demonstrated by the prototype:

• Continuous processing enables steady-state conversion of powder to uncoated tablets within minutes.

• Rapid deployment (i.e., design, construction, and implementation of a facility in less than one year with practical options for redeployment) is possible.

• Identical equipment can now be used for clinical and commercial manufacturing, effectively eliminating the uncertainty and significantly reducing the costs of traditional development to manufacturing and site-to-site technical transfers.

PCMM modelPharmTech: What are the advantages of the four aspects (portable, continuous, miniature, and modular) of the PCMM model and how do they relate?

Steiner (GEA): The key point is that continuous processing is the element that enables process intensification. Continuous processing and the manufacture of smaller product quantities in a continuous manner mean that machinery product-contact surfaces are becoming much smaller. Hence, the equipment is becoming smaller, more portable, and by definition, modular. So, there are four elements: continuous processing is enabling miniaturization; miniaturization is allowing processing systems to become portable and modular. And when you put all that together, you get the PCMM paradigm.

O’Brien (Pfizer): Continuous processing technologies have been around for more than 50 years. In the pharmaceutical industry, we have been at the point where processing equipment can routinely be configured in a continuous or semi-continuous manner for quite some time. Of greater importance is that our new paradigm shift has enabled dramatic reductions in size (miniaturization), which in turn begets true modularity. Reduced footprint, in combination with true modularity, allows processing trains to be enclosed in dramatically smaller, autonomous, GMP-compliant spaces at a relatively low cost. As a natural consequence, the self-contained processing entity no longer needs a traditional ‘brick and mortar’ factory infrastructure. Portability enables strategically driven redeployment options and allows the facility to be classified such that accelerated capital depreciation is possible.

Jornitz (G-CON): The PCMM model is the manifestation of the industry’s vision and need for flexible and rapidly deployable manufacturing systems. Future facilities won’t necessarily be large-scale, dedicated, single-product sites, but smaller, more agile manufacturing facilities that comply with the central tenets of FDA’s “Quality for the 21st Century” initiative. These agile production sites will be modular--or podular--and designed to be mobile. Continuous manufacturing, used in both OSD applications and bioprocessing, will support the benefits that can be gained from miniaturized or small-volume production processes. The PCMM consortium is exploiting all these options to fully optimize the efficiency and flexibility of future production processes.

PharmTech: What scale is meant by “miniature”?

O’Brien (Pfizer): We expect to operate within a range of 5 to 30 kg per hour, which roughly translates to an annual capacity of 0.5 to 1 billion uncoated tablets per year.

Steiner (GEA): Comparing batch processing with continuous systems is difficult in terms of absolute numbers, but the footprint or volume of such a system could be up to 60-70% smaller than a conventional installation. Being continuous actually eliminates the question of scale: the only factor is time. The equipment is physically smaller, but as it’s run continuously, it’s easy to manufacture production-scale volumes of product. There’s no need for scale-up any more or long product transfer times from R&D to full-scale manufacturing.

ChallengesPharmTech: What do you see as the biggest challenges in employing the PCMM model?

Steiner (GEA): From my perspective, I would say that we’ve not really encountered any insurmountable hurdles. Regarding technical challenges, the miniaturization aspect was challenging, but we found solutions. Economically, we’ve discovered that the system price for the PCMM compares very well with traditional models and actually offers a lot of advantages, especially in terms of its portability, flexibility, and productivity. The whole system was put together with existing equipment, including the commercialized CMT continuous inline blending technology from Pfizer. We didn’t have to invent anything new; we’ve just put it together in a smart new way.

O’Brien (Pfizer): There is a body of work around achieving regulatory understanding and ultimately their acceptance of both the technology and general paradigm. FDA and EMA have expressed  support for and seem to expect broader implementation on continuous manufacturing in the pharmaceutical industry, but many aspects will need to be worked through in terms of what is required for regulatory filings and routine operation. Challenges also remain in moving from the batch test and release to a real-time release paradigm. It is unclear whether regulatory agencies in developing markets will readily embrace the new technology. We also anticipate that workforce planning and retraining will be crucial to the successful implementation of this new paradigm.

Future of continuous processingPharmTech: Do you have continuous manufacturing projects outside of PCMM?

Steiner (GEA): GEA’s ConsiGma is a multipurpose platform for continuous manufacturing that has been designed to transfer powder into coated tablets in development, pilot, clinical, and production volumes in a modular, compact unit. The system can perform dosing and mixing of raw materials, wet granulation, drying, tableting, or direct compression, including online PAT quality control, all in one system.

O’Brien (Pfizer): At Pfizer, we have a number of ongoing projects in various stages of development that are investigating continuous and semi-continuous processing technologies for both API and other drug product development and manufacturing processes. It should be noted that we are also working with global regulatory bodies to ease the adoption of PCMM and related advanced manufacturing technologies.
PharmTech: What role do you think continuous manufacturing (PCMM or other) will play in oral solid dosage in the next 5-10 years?

O’Brien (Pfizer): From our vantage point, it wouldn’t be a surprise to see PCMM and other related OSD continuous development and manufacturing paradigms ultimately become the new norm in the pharmaceutical industry.

Jornitz (G-CON): Continuous manufacturing will dominate facility and process designs, as well as the manufacturing modus.

Steiner (GEA): Continuous manufacturing will continue to grow. The pharmaceutical industry is facing increasing demands for faster supply chains, and continuous technology is an enabler of more flexible and faster routes to market. I reiterate the key aspect that continuous manufacturing is an enabler of miniaturization; the subsequent portability and modularity lead to ‘process excellence,’ which in turn, delivers ‘business excellence,’ saving both cost and time, improving manufacturing efficiency, and enhancing the output quality of the whole organization.