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Agnes Shanley is senior editor of Pharmaceutical Technology.
Can an Irish analytics company and its CEO bring pharma closer to 21st-century practice?
Based in Dublin, Innopharma Labs was launched in 2009 during the heady days of FDA’s Process Analytical Technology (PAT) initiative, when advocates of modern process control and industrial engineering predicted a major shift in the industry’s approach to quality control and manufacturing.
Years later, a full-scale shift may not have yet occurred, but concepts such as continuous manufacturing and pharmaceutical quality by design (QbD), and a redefinition of process validation, have begun to drive new, more modern approaches to drug development and manufacturing with an increasing number of approvals implementing these principles. Moving beyond its foundation in PAT and particle size imaging, Innopharma has responded by branching out into new areas that include automated process control, services, and education.
In January 2018, the company formally launched a new advanced manufacturing program based on the concept of predictive control, permitting “self-guided” granulation and sophisticated control of modified-release oral solid dosage forms. Enabling this move was a €13-million investment in Smart FB, a suite of technologies that include a data historian and cloud-based data repository, to allow manufacturers to achieve the benefits of more advanced process control for batch processes. The technology can be test driven at the company’s new dedicated process R&D facility in Dublin.
Company founder and CEO Ian Jones discussed these initiatives and industry trends with Pharmaceutical Technology.
While Innopharma is focused on the pharmaceutical industry, particularly formulation and manufacturing, it also serves the chemical, food processing, and solids processing sectors, and this knowledge informs the company’s technology platform. Jones will be discussing Manufacturing 4.0 at INTERPHEX 2018 in April.
PharmTech: When did you launch your advanced manufacturing pilot program and are you currently working with any industry partners?
Jones: We officially launched the pilot program in January 2018, after testing it with pharmaceutical companies during 2017. This work builds on the application development and sensor system integration with partners Glatt, a specialist in fluidized bed drying, and Colorcon, which focuses on formulation materials including coating.
PharmTech: Are you working with any academic partners?
Jones: Over the past seven years, we have collaborated broadly with academia for PAT, but decided to invest in hiring process scientists, engineers, and chemometricians and bring this expertise inhouse. Based on input from pharmaceutical manufacturers, we have also developed our own Smart FBX advanced development and manufacturing modular platform incorporating PAT sensors, data integration engine, secure data storage, analytics and automated control components.
PharmTech: Why did you feel this was necessary? After all, can’t companies currently source the individual technologies (e.g., data historians and process control platforms) separately, themselves?
Jones: We felt that it was important to bring everything together. As mergers and acquisitions have become the norm in pharma, companies are managing a more diverse and global network of manufacturing sites than ever before, and contract manufacturing organizations (CMOs) are becoming a more prominent part of these networks. Our goal is to provide process data visibility, and to enable global access to development and manufacturing data so that we can support process development projects, wherever in the world they are based. Where companies lack in-house resources, our staff can step in and help with development and control problems.
PharmTech: Why do you see advanced control as being so important to pharma’s future?
Jones: Just consider a car or cell phone from 15 years ago and compare them to what exists today. They are almost completely unrecognizable. A high level of advanced analytics and diagnostics has been built into these devices which has become standard in these industries, but this is not yet the case for pharma.
If the pharmaceutical industry wants to develop and manufacture safer and more affordable medicines faster, improved automation and process control will be key enablers. That’s why we’ve gone down this road. At this point, the goal is not to pioneer, but merely to start to catch up to what other industries are doing with automation and analytics.
Smarter control will be especially crucial for scaleup and tech transfer. More, and better, technology is needed to support this work in the pharma industry.
PharmTech: What do you see as being responsible for pharma’s conservatism?
Jones: The main reasons are financial and regulatory. Today, the basic focus is on doing more with what you have, rather than investing in new technology. There is also an understandable conservatism to moving away from the traditionally accepted regulatory path in case of delay to approval or a request for significant additional data for a variation submission. As a result, it has been a major challenge for tech providers and the industry to get to a stage where advanced manufacturing is even possible.
Continuous manufacturing has been a great eye opener for many pharma companies, because it has helped them understand the potential role that feedforward and feedback process control might play in their operations. Quality experts at pharmaceutical companies often see moving from batch to continuous as being too risky, so the groups leading continuous manufacturing projects are typically those charged with starting a new process for a new product. Nevertheless, as more companies support the continuous concept, even at a very limited level, it is opening the door for them to accept more innovation, especially in automation.
PharmTech: Are you currently working on continuous projects with clients?
Jones: We’ve worked on continuous since 2009. Advocates for continuous processing predict that 2% of all pharmaceutical products will be made that way by 2020. Companies are moving ahead with continuous, and all the major equipment suppliers are offering platforms but the industry isn’t jumping as quickly as many people expected it to at first.
PharmTech: Is Smart Batch a response to these issues?
Jones: Yes, in a sense we have stepped back. We still see continuous as pharma’s future, but for the present, why not retrofit existing batch processes, using the algorithms and controls that are needed to make them smarter?
PharmTech: How would Smart Batch fit in to process development, or is it mainly for manufacturing?
Jones: There is no standard approach to control for process development. Everyone is trying to figure out how to optimize development to get to market as quickly as possible and meet QbD requirements with a risk-based approach to design of experiments (DoE). Fluidized bed processes tend to have a higher regulatory risk profile for chemical, manufacturing and control (CMC) strategy, so we are working on a systematic approach.
But automated control is much more relevant during product commercialization. Algorithms can react to various permutations in the process to bring automated dynamic process control, but nobody has gone on that journey yet, and we’re trying to figure it out. Customers clearly need to make batches smarter, however.
PharmTech: How do self-guided coating and granulation processes work?
Jones: They bring ‘hands off’ manufacturing closer to reality, using PAT to track critical process parameters and the product’s critical quality attributes during processing. Then, they use a model to control the process phase changes, including endpoints, automatically.
In addition, the technology is being developed so that these processes can be monitored remotely in real time from anywhere in the world, even, potentially, from a smart phone. In time, advanced manufacturing will facilitate real-time release and continuous processes.
Manufacturers around the world are supporting more automation and greater visibility of data, with many pharmaceutical companies developing and evolving plans for Pharma 4.0. There are considerable opportunities to increase manufacturing efficiency and regulatory compliance by implementing elements of Manufacturing 4.0. Improved control coupled with real-time process analytics provides process operators and supervisors with critical real-time information and reduces the risk of data transcription errors or deliberate falsification.
PharmTech: Why did you choose to focus on fluidized-bed (Wurster) coating and drying first, and why is control important to these unit operations?
Jones: First, fluidized bed coating is a multi-step process with potential for considerable variability, for example, due to raw material variation. Even where product is within specifications, bead size can change from batch to batch. Microcrystalline cellulose, for instance, is a natural material, so measurable qualities will vary, leading to varying process results. These variations impact product quality. Fluidized bed drying can also be difficult to control, which can have a big impact on the final product quality if the optimal level of moisture content is not achieved
PharmTech: How does that variability affect the quality of finished product?
Jones: Let’s consider Wurster coating. A typical pharma manufacturer will use a fixed amount of coating material, assuming that the beads are all the same size. But if you add the same amount of coating material each time, even a 20- to 30-micron difference in the size of individual bead diameters will result in different coating levels on the beads which will impact the product performance as measured by dissolution profile.
So we are applying PAT concepts to coating to help ensure fixed particle size change so that users can get the same coating characteristics every time, despite variability in raw materials and other factors. This approach uses advanced manufacturing principles.
First, the Eyecon analyzer is used to measure the initial particle size at the start of processing. The initial size data is automatically fed to a dynamic process-control algorithm that we’ve developed inhouse. That algorithm defines the trajectory needed to add the correct amount of material per minute to achieve to required coating thickness and stops the process once it has reached a predefined growth level.
The platform will be useful for developmental work, because it complements DoE software and allows product development teams to program and schedule development batches and access time aligned process and PAT sensor data such as PSD, moisture, spray rate, atomization pressure, air flow, temperature etc. on demand. Operators can then run the experiments, collate data, and run a sequential experiments. After each batch, users can access data to see how that batch did, and, after all runs are complete, they will be able to compare data and transfer key data to the DoE analysis tool. The platform makes definition of a design space and development of a process control strategy more efficient and makes data required for technical justification more accessible.
Jumping forward to controlling a commercial-scale batch, this setup would allow users to determine the optimal bead growth rate and terminate underperforming batches to ensure that rate is achieved.
Dissolution prediction would also be a crucial capability, but we will have to partner closely with each customer to determine the best approach, since every formulation will involve unique challenges (e.g., whether using water based or solvent based coatings, or different levels of API).
We will be focusing on fluidized bed coating for the next two years, and haven’t yet decided what the next step will be.
As the industry becomes more comfortable with remote data access, users would be able to view data via smartphone, laptop, or tablet using a 21 Code of Federal Regulations (CFR) Part 11-compliant data structure.
PharmTech: How does this platform embrace the concept of the Internet of Things?
Jones: Through its use of process equipment sensors and additional PAT sensors for critical process parameter and quality attribute measurements, cloud-based architecture and artificial intelligence, in the form of dynamic process control and the use of algorithms, and, ultimately through remote data access. We have talked with nine out of the 10 Big Pharma companies that use PAT extensively, and their feedback was very positive. We’ve also had positive feedback from equipment vendors, and the regulators are open to facilitate the adoption of new technologies. FDA appears to be leading the field with its most recent Pharmaceutical CMC Guidelines, “Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization Guidance for Industry.”
PharmTech: Are you focusing on one single equipment vendor or a limited number?
Jones: We will continue our long standing collaborationwith one vendor (Glatt), but expect to be able to retrofit to any customer’s or vendor’s equipment.
PharmTech: You had recently launched training and educational programs. What are your plans in that area?
Jones: As well as up-skilling thousands of students each year, we are in the process of launching our new online education program. It will first be available only in the European Union, but by the third quarter of this year, will be accessible from anywhere in the world.
This program fits in with our contract services in validation and scale-up support, which we introduced 18 months ago. Pharmaceutical manufacturers often have difficulty filling positions in these areas because there aren’t enough people with the right skills and experience to handle formulation development, scaleup, and manufacturing. With FDA’s new process validation guidance, there is a need for continuous process verification and the skills and technology required to support that effort.
Another focus for us, in both training and services, is project management. We have taken people without any pharma experience (e.g., professionals who have worked in the electronics industry) and given them 500 hours of validation and project management training and experience and found that they perform very well when placed into (bio)pharma environments.
PharmTech: Are you working in biologics?
Jones: At this point, we are focused on small molecules. In addition to our work in pharmaceuticals, we are also very active in the food and chemical industries, where we have worked on processes for infant formula and industrial solids materials. The experience is extremely applicable to oral solid-dosage form manufacturing, where there has been a real uptake in interest in automated control over the past three to four years.
PharmTech: What impact is outsourcing having on the way that pharmaceutical monitoring and automation solutions are being developed?
Jones: It’s hard to impose technology on a service provider. A contract manufacturer will generall make product with whatever tools the sponsor provides and supplement with support for process critical gaps identified during tech transfer planning. But the virtual company, Vertex Pharmaceuticals, has given the industry a great example of what is possible when the right tools are provided, in particular, for analytics and control.
Remote data visibility in real time has huge potential to improve outsourcing. One of the industry’s greatest challenges is the fact that, due to restructuring, the repositories of manufacturing knowledge aren’t there anymore. As a result, gaining real-time data visibility is very powerful. If a batch isn’t performing properly, this visibility allows you to react and intervene right away. As a result, we are getting some very positive responses from CMOs. Meanwhile, sponsors are using analytical technologies to profile processes at old sites and replicate them in new ones.
PharmTech: Your company came into being during the years following FDA’s PAT initiative. How fully has the industry adopted PAT?
Jones: I prefer to take a 20-year perspective on PAT. Back in the earliest days, before the FDA initiative, some people were using the concept and spending a lot on it, but they didn’t fully understand what they wanted it to do and how it would help them develop and control a process.
In addition, the technologies they were using had come from other industries and were not as fit for purpose as they might have been for pharma. For example, an analyzer might have been good for measuring cement but not the particle size diameters found in pharma excipients. In addition, much of the early equipment lacked compliance capability for pharma applications. Then along came the FDA guidance, which may have brought too much rigor to the implementation approach. The whole initiative seemed to go quiet for about 10 years.
Over the past five years, however, we have seen a renaissance in process analytical technologies. People understand the guidelines better and are more comfortable with them, and the industry is more mature in its approach to buying the technology that is required. At the same time, technology providers have invested a considerable amount of money in making their equipment fit for purpose in pharma, in particular, developing better, more user-friendly interfaces for pharma. We’re seeing much greater use of PAT for measuring moisture content and particle size for powder processes, and it is finding greater use in tech transfer. More generic-drug manufacturers are also using it.
PharmTech: Where do you see advanced manufacturing going in pharma in the short term?
Jones: It’s too early to tell, but there are already many initiatives in development to implement QbD principles to develop more defined, better understood processes. Efforts are increasing to apply automation, at least for end point control of critical process steps, often by combining process equipment sensors and PAT sensors to develop more sophisticated control. These are important early steps on the journey toward fuller automated process control.
One wonders what Elon Musk might do if he were to explore pharma. How would he get the molecule to the patient? The question is whether disruptive technologies will allow pharma to reach true patient-centered care and circumvent the status quo. Only time will tell, but we hope that our efforts will stimulate new thinking and help answer some fundamental questions.
Supplement: Solid Dosage Drug Development and Manufacturing
When referring to this article, please cite it as A. Shanley, “Innopharma Bets on Manufacturing 4.0," Pharmaceutical Technology Solid Dosage Drug Development and Manufacturing Supplement (March 2018).