Following the Science
Marketing new medicines is the lifeblood of any pharmaceutical company. Identifying promising molecules, progressing them through R&D, then to scale-up and development, to clinical trial testing and finally commercial scale production is the heart and soul of what every pharmaceutical company does. And indeed, a healthy pipeline of new products is what every company dreams of and aspires to accomplish.
With the ever constant need to develop and market new drugs many companies are looking to what are commonly referred to as potent compounds. This relatively new class of drugs has many uses but the major roadblock in developing these drugs is that, as the name implies, their potency can be highly hazardous to both humans and the environment.
So, for the companies that have decided to venture into potent drug development – the rewards can be very high – but also are the investments in facilities and equipment to contain these new drugs.
Roche has made a significant commitment to develop these drugs. The company recently opened up a new state-of-the-art clinical supply manufacturing facility on its campus in Nutley, NJ. The Roche Center of Excellence produces dosage forms of highly potent compounds for preclinical safety studies, and Phase 1 and 2 clinical studies. The 17,000 square foot facility houses specialized equipment to process potent compounds into medicines for clinical trials.
According to the members of the team most closely associated with the project: Waseem Malick, PhD, Vice President, Pharmaceutical & Analytical R&D; Dharam Singhal, Principal Scientist and Kevin Soltis, Principal Scientist – the dream of having a facility dedicated to developing potent compounds has been quite a journey, one in which the team has been actively engaged for many years. And as Malick says a very important facility for Roche’s future, “It’s quite critical. This facility is for oral dosage forms. But what is distinctive about it is we can handle highly potent compounds. You need containment for both protection for the people who work here and the environment. This is the only facility in the Roche group for clinical manufacturing which has that capability, which makes it very critical to the whole R&D process."
Everything about the facility has been carefully chosen, even the location at the Nutley, NJ campus. “It was a strategic decision to put it here,” says Malick. “We looked at different locations. Certainly we wanted it at an R&D site – which this is. The facility also had to fit into the site and the expertise that is available.”
As an R&D facility that furthers the development of promising compounds discovered by Roche researchers around the world, the facility had to be flexible enough to handle whatever comes through the door and yet manage to contain that same compound down to 50 nanograms which is Roche’s worldwide safety standard. Doing this was the challenge presented to the team. As Malick points out, “That’s (flexibility) a challenge for any R&D facility. You really want to have all options. That’s what makes an R&D facility different from a manufacturing facility where you have set processes. Here you have to be ready for anything that comes along. Innovation is a very important part of our business as well. Not only the usual technologies – but also to address – one of the big issues in the pharmaceutical industry and that is having a lot of compounds that are relatively insoluble. And because they are insoluble you can’t get the blood levels and exposure you need to treat diseases. So we have invested a lot in technologies over the years to address that issue. So in an R&D facility you need all of that. Because you have compounds with all different characteristics, there is a lot of flexibility – all different technologies - and batch sizes. And it changes from day to day, batch to batch, product to product.”
The facility and isolators were designed with the operators needs in mind. Ergonomics
was a big issue as the comfort of operators greatly influences safety and efficiency of
Indeed, as far as flexibility is concerned the facility is able to manufacture clinical scale products in several different dosage forms including tablets, capsules, solutions and suspension and powders. They also have a number of different unit operations – high-shear granulation, fluid bed processing, hot melt extrusion, roller compaction, compression, and encapsulation. Added on top of the different processes is the facility’s ability to handle different scales. Ranging from Phase 1 material amounts in the 1 – 10 kilo range to the Phase 11 range of 10 – 50 kilos – the facility needs a lot of different equipment and since they are handling potent compounds - all of it has to be contained.
A Unique Facility in Roche’s Realm
As a global company, Roche maintains the same standards for its operations globally. As far as containment goes Roche’s worldwide philosophy is that containment must be controlled through engineering controls – and according to Singhal, putting moon suits on operators was not the way Roche wanted to go with this facility. “If you compare this facility to several other facilities – the key thing that makes it stand out is the containment level. Roche has a philosophy that the operators who are using the equipment – the containment has to be controlled through engineering controls – to not rely on the moon suits operators wear. And that’s historically the way it’s been done in the industry. You can put a bubble around the operator and protect them. At Roche it’s the other way – we should have intelligent and effective engineering controls for containment – thus a person could be in a normal lab coat and be protected. And that’s what this is all about. This is the only facility in Roche that we know of that can do this – and we have a lot of facilities. We truly feel that the isolators in this facility are on the cutting edge with this kind of technology to protect our operators – that’s the safety part. We can have a very safe environment but it also has to be functional and that’s where the design of the isolators became very involved with the companies that built them. We wanted to make sure the operators can use them ergonomically.”
As can be expected, as the development and processing of potent compounds has become more commonplace in the industry, the technology to contain them has advanced as well. According to the Roche team the success of this facility has relied to a large extent on the expertise and involvement of equipment vendors, for in many cases there just isn’t equipment available “off-the-shelf” to do what is needed. In many cases existing equipment had to be modified and tested to ensure processing and containment levels are met. As Singhal notes, “It’s been a tremendous learning experience on the part of the equipment vendors. Containment and isolation have progressed tremendously over the last 10 years, especially in terms of how to approach it. We (Roche) certainly have grown as well.”
He continues, “There is a whole system we have developed: designing, buying, validating, training, SOPs, making sure there is a refresher course – it took us about 4 – 5 years to put it together.”
“I wish it was as easy as just buying the equipment and installing it – that would have made our life much easier,” he jokes.
How it all Works
The facility has seven processing rooms and over twenty hard shell isolators. Rooms are separated by function, each with its respective equipment in isolation. Incoming material is moved from dispensing to granulation to fluid bed drying, to blending, coating and then on to either compression or encapsulation.
All material transfers are made inside isolators, charged, processed and then double bagged at the output point and moved to the next room in the process train. As mentioned above much of the equipment has been modified for isolator applications with the addition of specially operated valves and the very important continuous bagging systems which have been added to all pieces of equipment.
The facility features seven processing rooms and over twenty hard-shell isolators. The facility is able to handle compounds that range from non-potent to highly potent. But as Soltis points out many compounds that come into the facility are not classified yet. These compounds have to be classified at the highest level of containment since the team is not sure what they are working with yet.
All unit operations needed to manufacture Phase I and Phase II clinical trial materials are available.
The facility is able to handle compounds that range from non-potent to highly potent. But as Soltis points out many compounds that come into the facility are not classified yet. These compounds have to be classified at the highest level of containment since the team is not sure what they are working with yet.
As a new facility, the team was able to make very effective use of space – and made sure that each room and isolator was supplied with all the essential utilities. As Soltis points out, “A real challenge of the facility was having the proper area for all the isolators. Height and width of rooms and doors is essential. This facility will increase our efficiency – all the isolators have their spot and won’t need to be moved.”
With its investments in technology and the facility, Roche is looking forward to the product development that can be achieved here.
Malick offers his perspective, “We have seen a lot of compounds that are highly potent in oncology areas – but we have also seen them in other areas - CNS (central nervous system) and neurobiology, even cardio vascular; very potent and effective compounds. But you need to protect yourself from these compounds.”
He continues, “The desire is to always have more and more important compounds. If you are going to go down that road then certainly the need for a facility like this is very necessary. Pipelines are driven by science. We go where the science leads us; which is why we have to have a facility ready to handle whatever comes our way. We have to make sure what comes in here we can develop from clinical trials through manufacturing.”