Cell Therapy: Process Commercialization Considerations

By: Erich Bozenhardt
Project Architect
IPS-Integrated Project Services, LLC

Would you pay $93,000 USD to extend your life by four months and would you relocate to one of the handful of treatment centers in the US for that therapy? Questions like this continue to propagate. Innovative and effective cell therapy treatments are advancing in the R&D pipeline, but costs and logistical challenges have been limiting the commercial success of the select therapies that have been approved. The considerations on the road to commercialization for cell therapy take on a higher level of complexity than those for biopharmaceuticals. For example, cold chain logistics moves from refrigerated cases of finished product handled by a distributor to shipping individual cryogenic units of sale. Additionally, new considerations come into play like administration through a medical device or a pre-conditioning treatment that are as much part of the process as the operations in a controlled manufacturing facility.

Some companies are betting on autologous therapies as the quickest and safest route. These therapies challenge us as an industry to deliver personalized medicine in a reliable and repeatable way. While the immediate goal might be successfully completing clinical trials, developing the process for scale-up and automation early on is critical to future successes. Removing operator variability by automating manipulations is one consideration. This can be a simple jig or the process could utilize a fixed bed culture technology that has an existing scale up/automation solution like a NuncTM Cell FactoryTM or Miltenyi Biotec Prodigy®. Developing the process to use closed systems can reduce the clean room space required, as well as the cross contamination risk. Gaining a deeper understanding of culture needs and how to meet those needs without a conventional incubator can also help the commercialization. Moisture loss concerns through vent filters and CO2 control have kept several processes locked into manual operations since the culture must be loaded into a reach-in style incubator.

During the development of the process for scale up and automation, logistics need to be considered. A Fenwal AmicusTM collects and processes the donation so that the desired fraction can be shipped frozen with a significantly longer allowable storage time versus a refrigerated whole blood donation.  As those donations arrive at the manufacturing facility, the management of what will become individual lots needs to be established. Barcode readers have been standard for a number of years and workarounds have been identified for frost over issues; however, cryogenic capable RFIDs can provide a simpler solution.

While autologous therapies provide a straightforward means of patient safety, specifically addressing graft versus host disease, researchers have developed allogeneic cell-based therapies that sufficiently address the safety concerns. Allogeneic therapies relieve some of the logistical complexity as a lot can provide therapy to many patients. Although donation logistics can be complex if the number of cell expansions are limited, requiring new donor material for every batch. Induced pluripotent stem cells (iPSCs) have the potential to allow for a traditional cell banking approach on human stem cell based therapies. Some allogeneic therapies take a different approach and utilize bacteria for cell therapies. One of the common commercialization considerations for all types of allogeneic therapies is the development of the culture to use

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Pharma’s (Virtual) Reality

By Stephanie Sutton, Editor, The Medicine Maker

One technology that caught our eye at The Medicine Maker in 2016 was augmented reality (AR) and virtual reality (VR). Most will admit that the technologies are “cool”, but at the same time there is a general feeling that the technologies are gimmicks that will see little use outside of the gaming industry or marketing campaigns. I actually thought the same thing until I researched the technology a little further….

Healthcare is one of the few sectors that has been using VR and AR for many years in very practical and inspiring applications. For example, VR has been used to provide patient therapies for pain reduction, post-traumatic stress syndrome, phobias, and even for teaching people to walk again. VR and AR are also being explored to help with training, with neurosurgeons at Duke University in North Carolina experimenting with the use of AR in delicate brain surgery.

The technologies are also making their way into pharmaceuticals. For example, Jonas Boström a drug designer based in the Department of Medicinal Chemistry at AstraZeneca in Sweden, has developed Molecular Rift – a VR environment where users can interact with molecules through gestures. Boström describes it as “the next generation of molecular visualization”. You can read more about his work on our website (https://themedicinemaker.com/issues/1016/entering-molecules/).

VR could also have a place in manufacturing. Last year, I spoke with Angelo Stracquatanio from Apprentice Field Suite to learn about how Google Glass inspired hands-free access to information for process engineers (https://themedicinemaker.com/issues/1016/harnessing-augmented-reality/). Basically, an AR headset is used to help with training, paperless procedures, and even safety and data collection; for example, an engineer wearing the headset can look at equipment and see information about it. The company launched at Interphex in 2015 – and was a hit. This application is actually very simple, but when you implement it on a practical level it can really change the way people work.

I’ve also been able to try out a VR tour of GE Healthcare’s KUBio. Wearing a headset, I could walk around a facility and even look inside equipment. It was definitely fun to try and also has a genuine use. Afterall, a facility can be designed on paper but it’s hard to know what it really feels like until you walk around it. I’ve also spoken with Pall’s Ian Sellick about this topic (https://themedicinemaker.com/issues/1016/virtual-facility-design/) – Pall has collaborated with a company called OUAT! to design a virtual space for users to build a laboratory or a whole facility. Users can set the dimensions and then look at where the utilities go and how equipment might be placed. You can do the same thing with engineering or architectural modeling programs, but the advantage with VR is that you can walk around it before building it.

VR is also useful when it comes to designing manufacturing equipment. Bausch+Ströbel, a supplier of pharmaceutical packaging machines, created a “Virtual Reality Center” in 2011 – VR is used in a variety of ways including virtual mock-up studies, design reviews, safety studies, ergonomic studies, failure mode effects analysis, training, machine redesign assessments, computer-aided engineering and air flow visualization. According to the company, VR saves a lot of time in project work and also allows customers to get involved in early project planning. You can read more about the project on our website (https://themedicinemaker.com/issues/1016/the-machine-maker/).

Overall, it seems like the use of AR and VR in pharma could be significantly more than just a gimmick – and I’ll be watching excitedly to see how the field evolves.

The Medicine Maker covers a variety of emerging technologies and trends in the pharma industry. Read more or sign up for a free subscription at: https://themedicinemaker.com/login/

 

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Risks to be Mitigated During Modular Construction

By: Don Hamme Senior Project Manager IPS-Integrated Project Services, LLC

A lot has been written about the benefits of using modular construction techniques in the Pharmaceutical industry. However, an area that is frequently not addressed is the risk, identifying and analyzing the risks that are present when using this approach.  All of the risks can be effectively mitigated but they cannot be overlooked if the project is going to be successful.

Most projects will incorporate some combination of modular and constructed-in-place elements. The interface between the two types of elements must be coordinated very precisely in advance to ensure everything aligns. If rework of the coordinated/constructed elements is required once the modules arrive on site, then there will be reduced cost and schedule impacts from using a modular approach. Very careful coordination with fierce attention to the details can prevent this situation.

Modules must be constructed with the correct tolerances to allow integration into the larger project. Fractions of an inch do matter.  Plumb, square, and level are just as critical. Module fabrication should be done by a company with a proven track record and successful experience in this area. Careful coordination of the interface details will not matter if fabrication tolerances are not followed.

Transportation of some modular elements like walls and ceiling do not pose a major concern unlike super skids and modularized building sections that can potentially be challenging. While the intent is to use modules that are as large as possible, shipping dimensions for the modules must be coordinated with the various requirements of each state the modules will travel through. Once the modules arrive at the project, the site logistics are just as important. Complete logistics plans for how the modules will arrive on site, be staged, and moved into and through the structure should be finalized well before the modules arrive. Delays and lack of coordination during this portion of the effort may result in additional exposure of the modules to weather risking damage to sensitive components, congestion on the project site, and an inability to move the modules to their final location.

All of the above risks can effectively be managed and do not offset the usually considerable benefits of modularization. Not addressing them can certainly impact both the cost and schedule benefits of modularization.

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Politics, Biosimilars and New Medicines and Technologies for the Future

By: Stephanie Sutton, Editor, The Medicine Maker

I’ve been writing about the pharmaceutical industry for close to a decade now. Part of what I love most about my current role is being able to report on a wide variety of topics and issues relevant to pharma, from ways to improve manufacturing efficiencies, to business trends, to groundbreaking research. Over the years, I’ve had the opportunity to speak with many truly inspirational and brilliant individuals. It makes me wish I had studied science rather than journalism at university….

I have been asked to write two blogs for this website. However, there are so many advances and changes happening in pharma at the moment that it is incredibly difficult to narrow things down to just two topics! Therefore, for this first blog I’d like to highlight a selection of key trends and advances in the industry that we have tackled in The Medicine Maker (https://themedicinemaker.com/) in recent months.

Political discord

When talking about current industry trends it’s impossible to overlook current global politics. Some of the biggest discussion points in the industry right now relate to the potential impact of “Brexit” and the election of a new US president. It’s not yet known exactly how these events will impact pharma – as well as other global industries – but it seems unlikely that it will simply be business as normal. In terms of Brexit, trade disruption is likely, as well as big changes for the European Medicines Agency, which is currently located in London. As for the US, President Trump’s actions are unpredictable, but the pharma industry has definitely been on the receiving end of his comments and speeches. He has also vowed to bring down drug prices.

In our February 2017 issue (see https://themedicinemaker.com/), George A Chressanthis, from Axtria, tries to predict what policy actions Trump is most likely to take and their potential impact on pharma. Policy actions on intellectual property protection and tax/financial reforms could be positive for pharma, whereas policies on drug pricing, labor immigration and international trade, are likely to have a more negative impact.

Biosimilars

The US finally approved the country’s first biosimilar in 2015. Biosimilars, of course, have been available in Europe for many years, but the opening of the US market was a crucial moment – and 2016 has ended with a long list of products under regulatory review. According to Eva McLellan and Martyn Smith, who contributed to the October issue of The Medicine Maker (https://themedicinemaker.com/issues/0916/bluff-or-serious-biosimilar-bet/), biosimilars are a hot topic for the industry because their impact extends across all phases of a biopharmaceutical product’s lifecycle – the issue of biosimilars is often raised in cell line development, manufacturing, analytical characterization and commercialization.

At the moment, the biosimilars industry is still finding its feet. Some early leaders have surged ahead, but the game could change – McLellan and Smith emphasized that the next decade will be a fascinating one to watch in terms of market dynamics. In the January issue of The Medicine Maker, Catherine Godrecka-Bareau (https://themedicinemaker.com/issues/0117/biosimilars-come-fly-with-me/) also argued that there is room for improvement in the biosimilars model; in particular, she explains that biosimilars companies could learn a thing or two from the airliner industry in terms of de-risking, optimizing costs and maximizing sales.

New treatments

Up until a few years ago, it was common to hear the media criticizing pharma for its “innovation drought”. The lack of innovation was attributed to a number of reasons, including the rising costs of research and development, and the economic crisis. Today, however, we are seeing continued successes in immuno-oncology and growing excitement around checkpoint inhibitors. There is also the rise of cell therapies and gene therapies. In January, we published a roundtable article (https://themedicinemaker.com/issues/0117/revelations-and-resolutions/) featuring Markus Thunecke (Catenion), Christa Myers (CRB), John Talley (Euclises Pharmaceuticals) and Eva McLellan (Roche) that I believe really showcases the fact that the future of medicines is bright. Siu Ping Lam, Director of the Licensing Division at the UK’s MHRA, also added: “Personally, I think 2016 has been a very exciting and busy year. A great number of new medicinal products have been authorized and the pharmaceutical industry is predicting that more new active substances are coming to fruition in 2017 and beyond.”

New technologies

Increasing innovation is also being seen in terms of new technologies that help improve the manufacture of drugs. A big focus for The Medicine Maker is on enabling techniques, technologies and processes that facilitate drug development and manufacturing. At the moment, “continuous manufacturing” and “flexible manufacturing” are key buzz words, with a number of new equipment launches being seen during 2016. Interesting advances are also being seen in formulation technologies, particularly in terms of overcoming API solubility challenges.

Every December, The Medicine Maker publishes its Innovation Awards (https://themedicinemaker.com/issues/1116/innovation-returns/). The Innovation Awards recognize the most exciting drug development and manufacturing technologies released over the year – with the overall winner for 2016 being MilliporeSigma’s Centinel technology. A variety of different technologies were highlighted in 2016 – and I think it showcases that the entire pharma industry, both manufacturers and vendors, is packed with innovation right now.

The Medicine Maker covers a variety of emerging technologies and trends in the pharma industry. Read more or sign up for a free subscription at: https://themedicinemaker.com/login/

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Beating the Serialization Clock

By: Optel Vision

By 2019, 80% of the world’s medication supply must be serialized, but only 30% of pharmaceutical packaging lines are currently equipped with serialization capabilities. This looming deadline ─ November 2017 in the US ─ is an enormous challenge for the entire industry, as the serialization process is a lot more complex than it initially seems.

Although the basic steps (printing codes, reading them, verifying them and ejecting non-compliant products) are relatively straightforward, that’s just the beginning. When we take a closer look, we realize that the difficulty lies not within the serialization operations themselves, but within everything and everyone required to make it happen on a daily basis. Main stakeholders include packaging, the warehouse, label control, validation, logistics, and many others, so the project can get very big, very quickly. This, of course, is in addition to the individual requirements of each packaging line and the numerous IT connections to a variety of systems, because all the data collected from the lines (like EPCIS reports, serialization results, e

tc.) must be reported to a database.

Meeting all these requirements takes time, not to mention a substantial budget, which can be yet an additional obstacle. Considering the currently low percentage of serialization-ready lines, many pharmas and CMOs might not make it in time for the deadline if they opt for a full-fledged custom system. Yet all these requirements still demand a highly adaptable solution that can be implemented in time. In response to this issue, some serialization partners have put together a line of preconfigured units, specially designed to be delivered before the deadline.

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Meeting Today’s Product and Personnel Protection Industry Requirements in Fill-Finish

By: BOSCH Packaging Technology

While today’s aseptic filling applications increasingly require the protection of both the product and personnel with elaborate air handling systems, automated decontamination processes, and the latest safety features, the growing need for specialized medicines produced in small batches means that efficient manufacturing systems also need to be flexible with short changeover times.

At this year’s INTERPHEX conference, and also part of the IPS Technology Tours (Aseptic Full-Scale & Flexible Technologies track), Bosch Packaging Technology will be presenting a case study on its FLT 1000 vial filler with Isolator, an offering designed to meet today’s increasingly challenging needs in fill-finish by providing a complete range of infeed and outfeed options to cover the wide variety of vial sizes, materials, and configurations (glass, plastic, and RTU components) handled.

Filling lines require competent management of the interaction between filling machine, barrier system, and preceding and subsequent machines. Challenges include the safe functioning of the interfaces, the simplicity of the overall controls system, and the ease of operation of the individual components. Interface resolutions between different manufacturers are often risky and time-consuming, and can delay projects by weeks, the start-up of individual subsystems failing to provide assurance that they will work properly together. The delivery of all components from a single source: isolator, machines, and processes from one provider, developed together and for each other, significantly mitigates these risks.

The Bosch FLT 1000 with Isolator fully integrated solution is a product of the close collaboration between three Bosch global sites: Bosch Minneapolis (filler technology), Bosch Crailsheim (filler and barrier technology), and Bosch affiliate Klenzaids in India (barrier technology and cost-effective manufacturing). This illustrates the depth and breadth of in-house technologies and capabilities that are necessary for adequate concept planning and successful implementation of today’s complex pharmaceutical fill and finish projects.

 

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A milestone in packing material and process development

By: Bausch + Stroebel

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KCP: The potential of this equipment has by far not been exhausted yet

With the KCP Bausch+Stroebel took the next evolutionary step into automation. Having a flexible filling platform with four configurable modular processing stations, our customers can simulate a variety of different industry standard dosing, closure placement, sealing, and inspection arrangements currently used in commercial production of parenteral products.

With two clean room robots, the filling and closing machine provides a wide range of applications for small batch production or process and product development. Virtually any customary container (vial, syringes, and cartridges; plastic or polymer or glass) can be processed on the line with minimal changeover time. Completely different work steps can be integrated in the work flow.

Up to four work stations can be integrated in the KCP as required and can easily be customized by the operating staff. To support cGMP traceability requirements and batch record documentation, Bausch+Stroebel has developed a system to verify if the selected size parts at the HMI match the size parts that are installed on the machine (HMI-prompted recipe verification of the size parts).

The two aseptically designed robot arms never cross between the laminar airflow from the RABS and an open container. They are always below the open containers, thereby ensuring first air is never broken by robot processing activities. The KCP is compatible with a RABS or isolator installation with optimized air flow verified with detailed Computational Fluid Dynamics studies (CFD).

The KCP is capable of testing the handling of a broad range of packaging material, such as plastic or glass containers (vials, syringes, cartridges), coated, siliconized or uncoated stoppers and plunger closures.

Furthermore, the KCP provides the possibility for In-Process Control (IPC) of up to 100% of the production batch or at regular predefined intervals, thereby ensuring documentation compliance of batch data.

Our customers are therefore in a position to evaluate all possibilities and risks during process development prior to production. Thus, they optimize packing material composition and product compatibility, thereby ensuring troublefree production and absolute process reliability.

The filling, stoppering, crimping and control technologies on the KCP are fully scalable to other high speed production lines. All batch parameters are transferable and applicable to high speed production.

Furthermore, a big advantage for our customer is to have that knowledge and testing possibilities at their site.

With the KCP, Bausch+Stroebel can supply an extremely flexible filling and closing machine for comprehensive development and small batches (the model at the Interphex can process up to 1,000 containers per hour).

High flexibility and time saving are the advantages for the user of the newly developed KCP.

The KCP5060 gives ultimate flexibility to test any packaging material configuration provided that the appropriate change parts are installed. Our best example of the breadth of flexibility available is the custom KCP5060 purchased by West Pharmaceutical Services. West is currently testing 7 different containers (vials, syringes and cartridges), 21 different closures (stoppers, seals, caps), 5 filling and closing processes (rotary piston, time/pressure, peristaltic, sensor filling, and vacuum filling and closing) in 98 different configurations (bulk feeding and RTU components) on their KCP. The range of processing sequences the robot-equipped KCP is able to cover is enormous. However, the full potential of this equipment has not yet been realized. New applications are continuously identified and the system can be expanded at any time for additional future processing capabilities.

Erik Anderson, Principal Product Development Engineer from West Pharmaceutical Services states how the KCP is applied at West and how it enhances the product development life cycle:

“To characterize the performance of all fill finish process variations as well as all closures, seals, vials, cartridges and syringes (commercial and prototype) requires the use of an extremely robust, innovative, and flexible filling platform. After much scrutiny via a West user requirements matrix vetted against a wide range of well-established OEMs, this project was ultimately awarded to Bausch+Stroebel because of their ability to meet the majority of user requirements, innovative culture, track record of proven performance, and technical competency.

Since project inception, multiple challenges have been overcome, processing capabilities have increased, and new applications for the use of this custom filling platform have been identified. Some of these applications include performance characterization of containers and closures, machinability performance evaluations, and testing of novel fill finish process improvements. West is very pleased with the progress to date with Bausch & Stroebel and is looking forward to continued success.”

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