As blockbusters fade and biologicals or personalised medicines come to the fore, traditional high volume facilities are being replaced by small scale, flexible plants and single-use technologies. Susan Birks reviews the year’s process trends, equipment and analytical tools.
The production facilities of the pharmaceutical world are changing at a faster pace than ever before. This is in part due to the rapid discoveries and progress being made in biotechnology and stem cell technology but also to increasing regulatory and health authority demands for better performing, more sustainable and consistent products. As a result, we are seeing increased use of PAT and Quality by Design (QbD) principles as demanded by the regulators. There is also the ever more critical need to drive down costs.
In particular, the trend towards personalised medicine and more targeted products is driving the need for better containment for highly potent substances, smaller batch sizes, and the growth of biopharmaceutical production – which brings with it a host of new technologies involving fermentation, cell culture and use of disposable technologies.
New plants are being designed for flexibility and low volume production
New plants are being designed for flexibility and low volume production. Cleanrooms are becoming more multipurpose and containment is being concentrated more directly around the processes, with an increased use of automation to reduce worker exposure to potent ingredients.
A good example of this trend is the facility recently opened by Rentschler Biotechnologie, which was winner of the 2012 ‘Facility of the Year’ Award for the category of Equipment Innovation. At is facility in Laupheim, Germany the design of its fully configurable, multipurpose cleanroom suites helped it win the accolade.
Its other winning concepts included: the creation and use of a customised single-use preassembled manufacturing kit; its development of a highly automated skid for virus filtration; and achievement of a 40% reduction of fixed operating costs for the facility.
To achieve that kind of cost reduction Rentschler made its facility design 100% mobile and introduced standardised single-use equipment, employed debottlenecking process models and designed processes that allowed direct scale-up from 25ml to 1,000 litres.
The widespread adoption of biopharmaceutical manufacturing is seeing the introduction of new facilities that allow for rapid product change and a high level of contamination control. For example, global contract manufacturer Catalent announced recently that its Catalent Pharma Solutions division will relocate to a new plant in Madison, Wisconsin, US, that will enable a switch from stainless steel to single-use bioreactors, increasing capacity by extending the number of batches produced per suite and providing it with greater flexibility in the scale of cGMP manufacturing capacity.
plug and play flexibility
Such moves are aided by the development of simple plug and play single-use equipment and components. Active in this area, equipment designer GE Healthcare went on a European tour this year in a specially designed truck kitted out with a complete suite of flexible, single-use products configured for vaccine or MAb production.
It believes that with the increasing potency of drugs and the growth in personalised medicines, the single-use route to biotech manufacturing offers several key advantages: eliminating cleaning requirements, thereby increasing the speed of campaign turnaround; reducing the risk of cross-contamination; cutting the time to market because of shorter lead times; reducing validation time and costs; and requiring much lower capital expenditure.
Merck Millipore is another supplier developing products for this sector. Its recently introduced Mobius SensorReady technology is designed to monitor and control a 50 litre bioreactor, offering the flexibility to configure process monitoring at the point of use, while reducing the need to customise bioreactor process containers and enabling easy integration of new sensor technologies. With this introduction, biopharmaceutical manufacturers now have a wider range of scalable single-use bioreactors – from 3 to 200 litres.
We've integrated a number of features that deliver ease-of-use, reliability and operational flexibility
Paul Chapman, vice president of Merck Millipore’s Biopharm Process Solutions, says: ‘The Mobius CellReady 50 litre bioreactor is an important addition to the Mobius family. We’ve integrated a number of innovative features that deliver ease-of-use, reliability and operational flexibility compared with existing single-use systems.’
Major players such as Sartorius are investing in the single-use market with the build of a new plant for the manufacture of bioreactors and production equipment in Guxhagen, Germany. It says its latest single-use components are connected to the product stream via sterile plug-and-play connections that can be easily removed, bagged and disposed of without breaking connections and exposing the environment to the product. It has spent a further €16m on a facility in Puerto Rico in response to growing demand for single-use products.
Another trend that the pharmaceutical equipment market is benefitting from is that of greater co-operation between suppliers to make more integrated products. Applikon Biotechnology, for example, which has a portfolio of measurement and control instrumentation and bioreactor systems, has partnered with Thermo Fisher Scientific to offer Integrated Advanced Applikon control systems with Thermo Scientific single-use bioreactors. The two companies have developed an integrated solution combining the Thermo Scientific HyClone Single-Use Bioreactor with Applikon ez- and i-Control systems.
continuous production & PAT
The quest for continuous manufacturing and greater use of process automation technology continues, but the conservative nature of the industry and the difficulties and costs of validating new systems means that advances are slow. In 2009, Siemens, GlaxoSmithKline (GSK) and GEA started a joint project to prove the feasibility of continuous manufacturing in terms of tablet production. By identifying critical parameters and directly controlling these parameters, the three companies were able to create a tablet manufacturing line that runs continuously, seamlessly processing powder into coated tablets; fully continuous manufacturing lines are now being offered to pharmaceutical companies around the globe.
Such a concept places huge demands on process control. Large volumes of data have to be taken from sensors, and based on these readings integrated control loops stabilise the process to be implemented.
As a result of its work with Siemens, GSK was able to ‘scale down its [plant] footprint, achieve granulation on a “grand” scale rather than kilo scale and also drying on a kilo scale.’ It was also able to understand, simplify and better control processes so that it could stop and start them at will.
In November 2012, the project won the Outstanding Achievement in Chemical Engineering Award and Chemical Engineering Project of the Year Award, from the – now global – Institution of Chemical Engineers (IChemE).
smart valves and sensors
As in-process measurement and control has become much more important, smart valves and new transmitters have been introduced along with better sensors. Sampling is a critical yet complex task for pharmaceutical manufacturers and is often one of the hurdles faced when looking to achieve QbD, says Kim Muro, North American director of sales from Alfa Wassermann Separation Technologies (AWST). The challenge has been to maintain aseptic conditions, but with its new product, Empat, the supplier of ultracentrifugation equipment for biologics manufacturing claims to be achieving this goal.
Empat is an automated sampling system for research, product development and commercial-scale biopharmaceutical manufacturing. It collects samples directly from bioreactors aseptically and automatically, saving time, removing the risk of potential error and improving the precision of quality control measures.
Empat is designed to guarantee the industry achieves a state of continual improvement
AWST says the system is easy to install and programme, operates continuously around the clock and integrates seamlessly with existing data systems, giving users real-time process characterisation. ‘Empat is designed to guarantee the industry achieves a state of continual improvement,’ says Muro, adding that: ‘Proper utilisation of Empat delivers an increased level of scrutiny for manufacturers that more than satisfies industry requirements to ensure process verification’.
Stratophase, a UK developer of advanced sensor systems has added the Ranger system to its portfolio for the biopharmaceutical industry that provides real-time, in-line bioprocess monitoring and fermentation control, to increase yields of biologics. The Ranger can be integrated into all bioprocessing systems running microbial or mammalian cell cultures, and enables bioprocess managers to monitor and control metabolic rate, observe batch processing trends, and accurately determine end of process.
Ranger monitors the composition and temperature of the bioprocess culture and gives instantaneous insight into process kinetics. It can be used to determine both the relative batch quality, compared with previous process trends, or to identify and react to key process characteristics. The control units allow four or eight probes to be deployed in parallel and are designed for laboratory bench-top use, pilot-scale environments and full production scale.
Ranger will enable users to improve consistency, reduce waste and increase yields
Dr Sam Watts, business development officer, and founder of Stratophase, says: ‘In the design and development of Ranger we aimed to address Process Analytical Technology, the US FDA’s call for improvements in bioprocessing through advanced monitoring techniques during manufacture. Ranger will enable users to improve consistency, reduce waste and increase yields in their biopharmaceutical manufacture processing.’
In yet another example a new carbon dioxide (CO2) sensor from Mettler Toledo combines precise and reliable determination of dissolved CO2, with the performance benefits of Intelligent Sensor Management. Errorless measurement and diagnostics that predict when maintenance will be required improve process safety.
In striving to achieve the goals of the FDA’s PAT and QbD initiatives, the in-line monitoring and subsequent control of CO2 during fermentation processes can be of great value. Real-time, in-situ monitoring of the dissolved CO2 levels in the fermentation medium allows timely action to be taken to maintain ideal process conditions, leading to higher yield and product quality assurance, says the company.
materials handling
Advances are also being made in some of the more traditional areas of mixing, drying extrusion and granulation. Here companies are looking for reduced process times, better scalability, flexibility, ease of cleaning and reduced footprints.
For example, a new 762mm Vibro-Bed circular fluid bed drying system from Kason is said to increase operating efficiency, cut cleaning time and reduce cost. New Jersey-headquartered Kason says the rigidity of the circular fluid bed processing chamber exceeds that of traditional rectangular fluid bed processors, allowing construction materials to be down-gauged and vibratory motors to be downsized. Associated components are also eliminated, such as multiple air inlets and outlets, the circular unit requiring only one of each.
As a result, the dryer is said to be lighter, stronger and more energy efficient at equivalent capacities. Cleaning time is cut in half due to stainless steel material contact surfaces, reduced weld seams, a quick-disconnect housing, and lack of internal cross members.
The compactness and light weight allow complete systems to be configured or modules containing the blower, heater and programmable controls to be assembled on skid-mounted frames, requiring only on-site connections to a power source, dust collector, and material inlet/outlet.
Today's researchers face multiple challenges, from resource constraints to limited lab space and budgets
Thermo Fisher says that today’s researchers and scientists face multiple challenges, from resource constraints to limited lab space and budgets. Its Pharma 11 extruder is designed to meet these challenges by delivering a small, simple-to-use and scalable piece of kit. Charndeep Khattar, director product line Process/Pharma Instruments at Thermo Fisher says: ‘With its compact footprint and minimal sample material use, Pharma 11 simplifies the testing process and enables scientists to focus on delivering world-class pharmaceutical research.’
In the materials handling sector too, equipment manufacturers and technology providers are combining expertise to create products that address industry needs. For example, Malvern Instruments, along with collaborators ARTMiS and Powder Systems (PSL), have created a new milling suite that incorporates ARTMiS’ Automated RealTime Milling System within PSL’s containment unit, which is designed to provide a secure, advanced processing solution for highly potent or high value materials.
ARTMiS brings Sturtevant’s Micronizer jet mill together with a Malvern Insitec particle size analyser and the Schenck AccuRate PureFeed Feeder to deliver a fully automated system for jet milling, aimed at providing exemplary process control for optimal manufacturing efficiency.
Built on the expertise of all three companies, it is designed to simplify and optimise the jet milling process and reduce operational requirements.
Meanwhile the industry often has to deal with highly potent substances, such as sex hormones, which require high levels of worker protection. For Haupt Pharma Munster’s potent products, Lödige developed a new tablet coater. The key requirements for the new system were processing of substances to occupational exposure band (OEB) value 4. Secondly, for production for the US market, the coating system had to conform to the CFR regulation Part 11 (21 CFR Part 11) issued by the FDA.
Besides its compact design, the main feature of this coater is the horizontal coating drum with four exchangeable perforations. Only about 25% of the cylindrical drum section is perforated; the coating drum itself is closed to the outside – a prerequisite for use within the high containment system.
During the coating process, there is a vacuum in the coating drum to prevent the emission of product dust. After feeding and prior to emptying dust is also removed from the inside by a special compressed air blower.
flexibility end of line
End of line packaging operations are similarly affected by all the previously mentioned advances. A greater variety of products, with smaller batch sizes and frequent changeover, has led to the need for greater flexibility with packaging solutions. The latest filling and closing machines must be able to handle different sizes of stoppers, caps and vials, allowing for simple changeovers between low-volume production runs.
Combination products are a growing area that illustrates the merger between packaging and product, requiring integration and expertise from the packaging industry. The trends toward pre-filled syringes for vaccines and new biotech drugs all require new solutions in aseptic manufacturing and fill-finish activities. These complex manufacturing processes create many production challenges, and the frequency of failure is reflected in the number of headlines about drug shortages and quality issues.
Seeking a common automation technology platform for both processes can drive down costs
Automation is key, and Mike Abbott, from Siemens Industry Automation, believes that the two ends of the pharmaceutical production process should no longer be addressed as separate entities. He says that seeking a common automation technology platform for both processes can drive down costs, increase operational efficiencies and improve overall performance for the long term.
In the pharmaceutical industry the primary process will generate the active ingredients, but then the pill-making and packaging machinery processes are required to finish the entire process prior to shipment. However, despite the clearly linked status of both processes, manufacturing companies have often followed a traditional approach that views the automation platforms for each part of the primary and secondary processes as separate. This has led in many cases to duplication in cost and time as well as reduced efficiencies as companies adopt a silo mentality for two elements of what is, in effect, a continuous production whole.
‘Looking at the issue from a holistic standpoint, and viewing the manufacturing process as a continuum, adopting a common automation platform across the manufacturing operation will, over time, reap real dividends in many operational areas including expenditure savings for spares inventories, more efficient use of training man hours and a reduced potential for expensive production downtime,’ says Abbott.
In the secondary processes, for example, associated with machine automation on filling or packing lines, PLCs have dominated. However, Abbott says it is entirely feasible also to utilise the same units for distributed process control purposes at the same plant – supplied from a single supplier source.
information overload in the lab
The production facility and development lab are integrated more closely than ever before, both in terms of scalable equipment and in terms of information flow.
Trish Meek, director of Product Strategy, Life Sciences, Thermo Fisher Scientific, says: ‘As biopharmaceutical companies have evolved over the past 10 years, so too have the Laboratory Information Management Systems (LIMS) designed to manage laboratory processes and data.
Today, biopharmaceutical companies are driving towards a paperless laboratory
‘One of the biggest changes we have seen in that time, has been the move to QbD to reduce manufacturing costs while ensuring product quality. QbD requires a continuous feedback loop as a product moves through the development process to ensure a good understanding of the Critical Quality Attributes (CQAs) of the product and the Critical Process Parameters (CPPs) of the manufacturing environment.
‘Today, biopharmaceutical companies are driving towards a paperless laboratory where, through data integration, they have a contiguous process from initial instrument data acquisition to final decisions made at the enterprise level. Today’s LIMS is the central integrator connecting the laboratory to the rest of the organisation.’
Whether for QA/QC or development, analytical equipment used in today’s labs relies on ever more complex science yet it has to be both multifunctional and easy to use. Once the preserve of the specialist, the spectrometer, for example, has widely become the workhorse of the lab. Thermo Fisher Scientific describes its recently introduced Nicolet iS50 FT-IR spectrometer as the first research-grade FT-IR with one-touch operation.
The machine features purpose-built accessories and integrated analytical software capabilities to provide an all-in-one materials analysis platform to help solve analytical challenges with ease.
The Nicolet iS50 FT-IR – a research-grade FT-IR spectrometer with one-touch operation
For flexibility the system can be upgraded from a simple FT-IR bench to a fully-automated multi-spectral range system that can acquire spectra from the far- to the near-infrared. Users can initiate novel ATR, Raman and NIR modules at the touch of a button, enabling access to these techniques without manually changing system components. The Nicolet iS50 analyses complex mixtures and materials using its GC-IR or TGA-IR capabilities.
‘Today’s scientists must be more productive and possess a broader skill set than ever before,’ says Simon Nunn, global marketing director for Molecular Spectroscopy at Thermo Fisher. ‘In its simplest form, the Nicolet iS50 is a high-performance yet simple to use FT-IR spectrometer. When equipped with its optional modules, it becomes a powerful materials analysis workbench capable of extracting an incredible amount of information from a wide range of samples. All techniques are available at the scientist’s fingertips – literally.’
As pharmaceutical manufacturers struggle in today’s difficult climate, the equipment industry is realising that open collaboration with both clients and other suppliers towards a common goal will help all achieve their ultimate aims and may even mean more profit.
