From The Editor | June 19, 2017

Continuous Manufacturing In The Mediterranean Sea

Louis Garguilo

By Louis Garguilo, Chief Editor, Outsourced Pharma
Follow Me On Twitter @Louis_Garguilo

Continuous Manufacturing In The Mediterranean Sea

Well, not exactly in the sea. But on the picturesque island of Malta, where Big Pharma, universities, and European health ministry officials dove into the waves of continuous manufacturing adoption for drug development and production.

The gathering was entitled: Emerging Pharmaceutical Manufacturing Summit 2017: Oral Solid Dosage Continuous Manufacturing in the Current Regulatory Landscape.

Hey, any reason to go to Malta is a good one, right?

In fact, continuous manufacturing (CM) is a compelling reason for discussion around the globe, and has led to a number of articles in these pages. The main reason: The technology and methodologies have arrived.

Eli Lilly is manufacturing proof to what degree. Wyatt Roth, Research Scientist, Formulation and Process Development for Lilly, spoke at the Malta summit on his company’s strategy. Lilly has become well known as an early adopter of CM to accelerate new chemical entity (NCE) development and launch for oral solid dose. Lilly has developed a “default manufacturing platform” based on direct compression, and has implemented identical lines across R&D, clinical, and commercial manufacturing. The company has already processed 10 molecules through their facilities.

Sunny For CM, But Some Lingering Clouds

There’s more to the selection of Malta as the venue for this meeting than its picturesque setting. Malta – historic home to the Knights Hospitaller – has a long history in the advancement of health care. More recently, Brexit plays a role as well: The Maltese Medicines Authority would like Malta to be considered for the new location of the European Medicines Agency.

The summit was held under the banner of the International Institute for Advanced Pharmaceutical Manufacturing (I2APM), a global coalition of academic research centers. The Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) at Rutgers University, also served an active role in the gathering. The organization “focuses on advancing the scientific foundation for the optimal design of solid dose pharmaceuticals while developing the methodologies for their active control and manufacturing.”

Outsourced Pharma readers may recall a recent article on continuous manufacturing featuring Douglas Hausner, Ph.D., Associate Director for Industrial Relations and Business Development, and member of the Department of Chemical and Biochemical Engineering at Rutgers. Here are his key takeaways from Malta:

  1. The EU is witnessing an "open-arms" approach to CM, but with no specific guidance; this can been seen as challenging as companies look for more guidance on how to move forward from a technology and regulatory standpoint.
  2. To the extent possible, CM adoption will be aided by the creation and adoption of global harmonization for requirements, and standards and other support for equipment interchangeability, as well as a coming together of industry expectations.
  3. At least in the short term as technologies continue to overlap, regulatory flexibility towards small formulation changes, and parallel manufacturing of batch and continuous processes, will help to increase adoption.

We’ll tackle the regulatory environment in a moment, but first let’s visit some other comments we heard at the summit.

Anthony Serracino Inglott, Professor at University of Malta, compared CM to the scientific change that took place nearly half a century ago as the industry adopted pharmacokinetics, and shifted from an “art” towards a “science” of how medicines are studied in the human body. He believes today’s paradigm shift for pharmaceutical manufacturing is analogous, and collaborative engineering and science-based manufacturing is the path forward.

Professor Fernando Muzzio of Rutgers University outlined how CM provides a wealth of information that will completely alter the level of process understanding for manufacturing of solid dose pharmaceutical products. He commented: “Continuous processes produce more information each minute than a batch process produces for that entire batch.”

However – and here’s to a balanced discussion – Lawrence De Belder, Senior Principal Engineer Continuous Manufacturing, Johnson and Johnson (Janssen), while in agreement with the positives of the technology, did insert a degree of levity.

De Belder cautioned that the organizational changes and business drivers accompanying CM can be challenging to implement. Trust, says DeBelder, must be built across the organization to maintain a coherent vision, and chart a course for enabling change throughout the journey to the realization of full benefits of the technology.

He pointed out that there is much that vendors and others within the community can do to aid in making adoption smoother, including support for equipment interchangeability. He also mentioned that harmonization of global requirements, and regulatory flexibility towards small formulation changes – and specifically parallel manufacturing of batch and continuous processes – are key for the industry to build a durable CM supply chain. Which brings us back to regulation.

Regulating The Sea Change

Christine Moore, Executive Director and Global Head for CMC Policy at Merck’s MSD subsidiary, and a former acting director for the FDA, believes “the biggest challenge we have [to continuous manufacturing] is alignment,” a lack of which slows down the rate of adoption, and ultimately makes the business case for adoption more challenging. She pointed out the highest risks regarding alignment is to control strategies, and over the next decade, the ability to use multiple formulations during the transition when both batch and continuous processes may need to be maintained for the same product.

However, Robert Bream, Ph.D., Scientific Administrator at the European Medicine Agencies (EMA), reminded the assembled that generally speaking it is not possible to have products with different compositions under the same Marketing Authorization Application (MAA) marketed simultaneously. Pharma companies must be aware of how this can impact strategy for using existing product conversion as a means of building organizational experience with CM. This in fact has been the approach of many first adopters of continuous pharmaceutical solid dose manufacturing.

Ding Ming, the VP of Innovation at the United States Pharmacopeia (UCP) spoke about what his organization is doing to support CM innovation globally. The USP sees continuous manufacturing as part of the future of pharmaceutical production, and is building the capability to support this innovation, including with new guiding documentation and standards. The USP, which relies on volunteers and experts in the field, recently convened an expert panel dedicated to CM.

Overall, the conference made clear that any remaining uncertainty for continuous manufacturing is less about technical capability per se, and more about strategic implementation, and what the conditions should be for regulatory approval. And although it’s hard to leave Malta, we’ll wrap up this conference review with Hausner: “In less than two years’ time, we will have seen the complete wave of first adopters enter the market with continuous processes.”