C-SOPS

C-SOPS and I2APM Present

OSD Continuous Manufacturing in the Current Regulatory Landscape 

 

On May 9, 2017, a unique gathering occurred in the middle of the Mediterranean Sea, on the small Island of Malta, where pharmaceutical continuous manufacturing was the topic of the summit.  The group gathered consisted of key industrial adopters, academics from across the globe and several European Union health ministries.   The summit was held under the banner of the International Institute for Advanced Pharmaceutical Manufacturing (I2APM), which is a coalition of academic research centers from across the globe.  This summit was focused on oral solid dosage pharmaceuticals, and The Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) based at Rutgers University in New Jersey, USA, which focuses on solid dose continuous manufacturing was highly visible. Today, as the market begins to truly adopt continuous manufacturing commercially across the industry, first through solid dose, we hope to maintain a community of practice that can aid in the transition by convening, researching, and training the next generation of contributors to the field.  

 

Malta’s deep history in healthcare and the passion of those working at its health ministry helped to catalyze the meeting and their chairperson, Professor Anthony Serracino Inglott, started off the day. He shared his experiences and related continuous manufacturing to the type of scientific change that took place nearly half a century ago as the industry adopted pharmacokinetics and shifted from an art towards science with regard to how medicines are studied in the human body.  He pointed out that today’s paradigm shift for pharmaceutical manufacturing is no different, and that collaborative engineering and science based manufacturing is what pharma needs. 

 

After the program introduction, Professor Fernando Muzzio of Rutgers University highlighted the various ways that continuous manufacturing provides a wealth of information that completely changes the level of process understanding for future manufacturing of solid dose pharmaceutical products.  He pointed out that “continuous processes produce more information each minute than a batch process produces for the entire batch”. Following Professor Muzzio was Lawrence De Belder of Janssen Pharmaceutical, who reiterated the remarks of the previous speaker with regard to information and process understanding, but added the caution that the organizational changes that accompany continuous manufacturing business drivers can be challenging to implement and trust must be built across the organization in order to maintain the vision and course for enabling change throughout the journey to realize the benefits.  He pointed out that there is much that vendors and others within the community of practice can do to aid in making adoption smoother, including creation and adoption of standards and other support for equipment interchangeability.  Also, harmonization of global requirements, regulatory flexibility towards small formulation changes and parallel manufacturing of batch and continuous processes were mentioned as key for the industry to build a flexible supply chain using this new technology.

 

Within the late morning session, the topics shifted towards the regulatory landscape.  First, Christine Moore, now the Executive Director and Global Head for CMC Policy at MSD in the United States, but formally of the FDA, spoke on potential regulatory challenges for continuous manufacturing adoption. She remarked that the “biggest challenge we have is alignment” which is slowing the rate of adoption and making business cases more challenging. More specifically, she tiered some potential risks, with the highest being related to alignment on control strategies and the ability to use multiple formulations during the transition over the next decade when both batch and continuous processes may need to be maintained for the same product.   To illustrate the logic behind continuous manufacturing, she presented a reverse analogy using the old needle in the haystack to depict our current batch process approach as throwing a handful of needles in a haystack, shaking it, and assuming a homogeneous distribution afterwards. The following speaker, was Dr. Robert N Bream of the European Medicines Authority, an appropriate follow up that by and large painted the picture of an open if not encouraging approach to continuous even without explicit regulation or guidance, though with an important exception that echoed the previous speaker.  Today, it is generally not possible to have products with different compositions under the same MAA, marketed simultaneously.  This is something which companies must be aware of as it may greatly affect the strategy of using existing product conversion to continuous as a means of building organizational experience with continuous manufacturing.  This has been the approach that many first adopters of continuous pharmaceutical solid dose manufacturing are taking. 

 

The afternoon session began with an I2APM academic panel where the different academic centers currently involved in advanced pharmaceutical manufacturing spoke about their individual capabilities and activities within the field.  The purpose of the panel was to demonstrate the worldwide network available for both industrial and regulatory support, and while these types of open and pre-competitive research efforts are important to other technology introductions, it is perhaps more important if not critical within a regulated industry like pharma. Following the academic panel, Wyatt Roth of Eli Lilly presented the company’s strategy for pharmaceutical solid dose continuous manufacturing.  Eli Lilly’s strategy is to accelerate NCE development and launch using continuous manufacturing.   To do this they have developed a default manufacturing platform for OSD based on direct compression and implemented identical lines across R&D, clinical, and commercial manufacturing.  With more than 10 molecules processed through their facilities already, it seems likely that we will hear more about the products and approach in the coming months.

 

In the mid-afternoon timeslot, Ewan Norton of the MHRA shared his experience on ‘early adopter’ continuous manufacturing inspections.  Ewan was the second active regulator to speak on the day, providing the post approval aspect of continuous process implementation.  The takeaway message was that, for the most part inspections involving continuous processes are no different, and that at least today the overall facility risk rating is not influenced by whether continuous processing is done there or not.  With regard to items that might be more relevant or prevalent for continuous processes versus batch ones the most significant seemed to stem around in-process testing and aspects related to malfunction/redundancy or calibration.   This was an unintended, but excellent segue into the following presentation by Robert Meyer, the Head of Innovation & New Technology Development at MSD.   

 

Robert Meyer’s presentation was on sampling and control strategies for continuous direct compression and it built on the key aspects of increased information and related process understanding emanating from continuous manufacturing processes.  The work demonstrated that a well-developed process model working with parametric feeder control can be more robust and significantly less variable than an in-line analytical method and advocated this as MSD’s choice for control feedback with analytical methods used separately for “sampling”.

 

The late afternoon session focused on international coordination and what I2APM and other organizations are doing to aid with the adoption of continuous pharmaceutical manufacturing. Professor Alberto Cuitino of Rutgers University spoke about public private partnerships activities supporting international adoption, which further emphasized the academic panel and the worldwide network available for both industrial and regulatory support.   Following Professor Cuitino, Ding Ming, the VP of Innovation at the United States Pharmacopeia spoke about what the USP is doing to support continuous manufacturing innovation globally.   The USP sees continuous manufacturing as part of the future of pharmaceutical production and is moving towards building the capability to support this globally with new guiding documentation and standards.   The USP relies on volunteers and experts in the field and has recently convened an expert panel dedicated to continuous pharmaceutical manufacturing.  

 

The 2017 Summit on Oral Solid Dosage Continuous Manufacturing in the Current Regulatory Landscape took place during a crossroad for the adoption of the entitled technology.   In less than two years’ time, we will have seen the complete wave of first adopters enter the market with their first continuous processes.  Key aspects related to regulatory perceptions and the clarity which will come with time even without explicit guidance documents along with important technical facets which need to be further explored were discussed at the summit in Malta this May.    From a regulatory standpoint, we will continue to learn by “doing” as the wave of first adopters of the technology pave the wave for the rest of industry, as regulators around the globe are unlikely to issue specific directives for continuous and will instead take an “open-arms” approach where you can discuss technology before full implementation and filing.  On the technical side, while there are enormous gains in available information and the potential related process understanding that can come from that, there are still limits that may need to be further explored in order to fully realize some of the benefits of continuous. While we may be able to design robust processes, and match the critical quality attributes of exiting products, uncertainly still remains when formulation changes are introduced relative to the batch process, even if this is for the purpose of better matching process performance and product consistency.  For some products, this is in part due to the difficulties in linking in-vitro methods like dissolution with

clinical performance.  

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Key Takeaways:

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1. In the EU we are see a seeing an "open-arms" approach to CM, but with no specific guidance, and we will learn much over the next two years from the first adopters paving the way. 

2. CM adoption can be aided by the creation and adoption of standards and other support for equipment interchangeability as well as harmonization of global expectations and requirements. 

3. Regulatory flexibility towards small formulation changes and parallel manufacturing of batch and continuous processes will help to increase adoption.  So, in the short-term flexibility on minor formulation changes when switching from batch to CM will be on a case by case basis.