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NIBRT's Michael Lacey provides an overview of biopharmaceutical facility design and operation.
In this sixth part of a series of primers with training experts from the National Institute for Bioprocessing Research and Training (NIBRT), Plant Manager Michael Lacey discusses the basics of biopharmaceutical facility design and operation. NIBRT provides training, educational, and research solutions for the international bioprocessing industry in state-of-the-art facilities. Located in South Dublin, it is based on an innovative collaboration between University College Dublin, Trinity College Dublin, Dublin City University, and the Institute of Technology Sligo. NIBRT opened a 6500-square-meters facility in June 2011 on a university campus in South Dublin City. The facility holds offices and training rooms, a pilot production plant, and research laboratories with supporting utilities, and offers a wide range of theoretical as well as hands-on training in all aspects of bioprocessing. The facility also has high-end research capability and process development and improvement capability. Lacey is responsible for facility, equipment maintenance, and support services to the plant's core business of bioprocessing, training, and research.
BioPharm: What do biopharmaceutical companies just starting out need to keep in mind in terms of planning a new facility's location and construction?
Lacey: There are many factors to consider in terms of choosing location, but some are key. First, the reality is that finance and commercial aspects are major considerations. The second category I would look at is the infrastructural side and the existence of support services. Finally, for me perhaps, the most important factor to consider is the people who run the factory. People are the most important asset a company has.
To expand on those three categories, let's look briefly at the financial and commercial side of things. Corporations are interested in corporation taxes, local taxes, and charges that they will pay in a particular location. They will be looking at their transfer pricing policy. They may have a treasury strategy. They may set up their financial headquarters in a particular location alongside their manufacturing base.
Companies will surely look at the availability of granted training support, and they will be very interested in their cost base; that is, the cost of labor, salaries, wages, transport, and shipping. Very importantly in the European context, companies will be interested in access to markets in certain countries, particularly European Union countries.
Looking at the infrastructural and support services side of things, manufactured product must be brought to the market. Therefore, effective distribution, including storage and freight transport by road, rail, air, and sea, are very important. With regard to a specific location, a company may prefer to set up where there is already a cluster of similar clients with similar requirements. If such a cluster exists, there is likely to be support services available such as laboratory services, maintenance services, project management, regulatory expertise, etc. as well as educational and research support from nearby institutes and colleges.
The third category, people, is based on who will operate and manage the plant. It is crucial to have a strong pool of talented people who are well educated, experienced, and flexible. Those people should also have continuing access to training and education.
BioPharm: In terms of specific facility operations, can you address the common needs for energy management in biopharmaceutical manufacturing? Also, what key things should companies look for when planning for these systems?
Lacey: Energy management is becoming increasingly important across the industry given that there is a strong green agenda worldwide and the need to reduce carbon footprint. There is also a very strong need to reduce cost base, and energy cost is a major portion of the operation cost of most pharmaceutical plants. Companies fall into a number of categories in terms of how they manage energy. For example, there are companies who manage energy very well according to national and international standards. They dedicate resources to energy management, and these resources make a big difference to operating cost. There are other companies who engage in energy projects and do quite well in terms of saving money, but perhaps, don't manage energy in a structured way. And then there are those companies who do not address energy issues at all.
Overall, energy must be factored into plant design and construction. It's particularly relevant to those who are looking at inward investment in new plant construction. New plant construction provides an opportunity to get energy management right. The problem that the industry faces in designing a plant is that it must comply with cGMPs and must be validated. Requirements for energy usage reduction can sometimes conflict with cGMPs, for example in relation to air changes, but I am convinced based on my experience that designers, production teams, quality teams, and engineering teams can work together to deliver an energy efficient plant that is also GMP compliant.
BioPharm: What other factors are at play with energy systems and cost?
Lacey: There are many opportunities to make gains in terms of the building, such as good insulation and draft-proofing, use of solar gains, natural lighting, intelligent lighting, compressed air usage, an optimum strategy for HVAC (heating, ventilation, and air conditioning), and use of alternative energy sources.
HVAC systems are major energy users, due to the requirement to make air changes in rooms and to condition the air. Air changes represent scope for cost savings. For example, if you have a Grade B room with a national requirement of 20–30 air changes per hour, the air change rate should be critically reviewed to suit the operation. At building design stage, room sizing (i.e., volume) should also be optimized. Thus, the air moved and conditioned can be minimized and so minimize energy usage. Most HVAC systems in pharma processing applications are "once-through". However, the use of recirculation systems should be adopted where possible as these are less expensive to run. Finally, room temperature control is key to optimizing energy usage. Room temperatures should be selected to suit the process and/or occupants.
Lighting is an appreciable proportion of a plant's energy usage. High-frequency fluorescent systems allow for dimmable lighting, so facilities can use dimmers to control the lighting in a way that it reacts to ambient light level. If a building has natural light, the fluorescent lighting levels can be dimmed accordingly. Lighting in public areas should react to presence and ambient natural light. "Intelligent lighting systems" should be considered.
Air compressors represent another area of opportunity for cost savings. Companies should analyze their air usage, and maybe use two or more smaller compressors rather than a single larger one. They should have variable-speed drives (VSDs) to allow maximum flexibility of response to demand. Most importantly, plant managers should ensure air leaks are repaired, as leaks can represent up to 30% of compressed air generation, and contribute significantly to energy wastage. In a medium size plant of 10,000 square meters, it can cost something like €60,000–70,000 (approximately US$78,000–91,000) per year to run a compressor.
Lastly, it's important to train staff about energy management. People use energy, and if they are taught good habits (e.g., turning off lights and monitors), then money can be saved.
BioPharm: You mentioned using two smaller air compressors instead of one larger unit. What benefit does this provide?
Lacey: As I mentioned, an air demand analysis needs to be done before that decision is made. Your air compressor supplier can do this for you. This improves response and "scalability" between air demand and compressor running. One plant I worked with had a single large compressor supplying the entire factory, and had a fixed-speed drive. The problem with this is that the motor either runs 100% or is off completely. This means that a large motor has to stop and start in response to changes in demand and this is not energy-efficient. A smaller unit fitted with a VSD can respond more flexibly. Using two smaller compressors also means that you have a backup in case one unit fails.
BioPharm: What considerations does a company need to consider with setting up and maintaining biopharmaceutical plant water systems?
Lacey: Pharmaceutical water technology is well established with a large number or reputable and capable designers and providers available. For purified water (PUW), a good system will invariably include reverse osmosis (RO) and electrodeionization (EDI), with ozone as a sanitizer. It is critical that the raw water is carefully considered and factored into design; not enough attention is given to the quality of mains water and the pre-treatment of it. I can highly recommend ultra-filtration (UF) as a pre-treatment technology, we have installed this in NIBRT with excellent results. For water for injection (WFI), distillation is mandatory in Europe and almost the norm everywhere. It's important to get the system sizing correct, especially if considering multiple-effect stills. For maintenance, it is important to get specialist help from the vendors; however, I can't over-emphasize the importance of comprehensive in-house monitoring by doing daily and weekly checks, this is a basic form of condition-based monitoring and is very effective.
Environmental aspects of water systems can be somewhat overlooked. We have talked about energy wastage; however, we also use and waste quite a bit of water in this industry. Pharmaceutical plants are generally metered by local authorities and they are charged by the cubic meter for water. This can be wasted in fairly innocuous ways. For example, PUW or WFI distribution loop pumps usually have "flushed" mechanical seals and the flushed water goes down to drain. It will look like a small flow, but this can drain a large tank over an extended period over 24 hours. The same applies to ozone sensors that are also flushed. So we waste a lot of PUW and WFI, which costs money, and depending on the location and the type of water plant, the cost can be very high—PUW is estimated to cost more than 60 cents per litre, WFI is more expensive, and so consider the cost of the loss of a 10,000 litre tank.
In terms of process, clean-in-place (CIP) is a common technology used in biopharmaceutical plants. It has the significant side benefit that it uses water efficiently. This technology is repeatable and reliable.
Of course we use water for more mundane reasons also e.g., drinking, washing, toilets etc. There are automated water controls that can be well utilized to save on water and cost.
BioPharm: GMP certification is important for the industry. What key GMP and cleanroom considerations need to be kept in mind if a company is trying to obtain GMP certification for its facility?
Lacey: The key points in terms of GMP are that the facility must suit the operations being carried out and must minimize any possibility of errors and contamination. Achieving this is all about adopting best-practice conceptual and detailed design, and so the design process is crucial. Assuming the right teams are in place with the appropriate skills and experience, the current building and process technology is such that, while it is an onerous task, it is relatively straightforward technically to build and validate a facility. Given the nature of our business, a somewhat conservative approach is best.
The increase in single-use and containment technologies offers opportunities. Where before critical operations may have taken place in a Grade A environment with Grade B background, newer technologies means that we can use rooms with a lower classification which are more cost-effective to build, maintain, and operate due to reduced energy usage, filtration requirements, and so on.
BioPharm: Control of facilities and their operations is crucial as is communication throughout the plant. Could you comment on these aspects based on your experience?
Lacey: I take this to mean "business control". In general, a company must have business systems that work well together, including planning, production, quality, and asset care. Systems should be integrated as far as possible with the same objectives.
In more specific areas, staff training is crucial in the biopharmaceutical environment. Companies must teach people upfront how to behave in a critical environment. Operators need to learn "off-the-job" so that less mistakes are made "on-the-job". The problem with training on the job is that mistakes can spoil or contaminate costly batches of product. So not only must companies train people upfront, but they must continuously carry out refresher training.
We also need to consider automation when talking about business control. The industry tends to think of automation in terms of direct control of specific equipment and processes, but a wider view should be taken. The larger multinational firms are well aware of this and practice such an approach. Automating business processes through the use of financial planning and control systems can help management at the higher business level, for example enterprise-resource planning (ERP) systems such as SAP.
At the process and equipment level, automation has been a feature for many years, with distributed control system (DCS) and supervisory, control, and data acquisition (SCADA) systems such as Delta V being commonplace. However, manufacturing execution systems (MES) are being increasingly used to bridge the gap between the high-end and low-end systems, providing shop-floor control of processes, and delivering strong benefits such as electronic batch records (EBR). Companies should avoid "islands of automation" and instead develop an automation strategy and integrate systems.
Asset care is also important—and I do not just mean maintenance, but rather, the lifecycle management of equipment and facilities. Computerized maintenance management systems (CMMS) or enterprise asset management system (EAMS) are tools that can greatly assist and automate asset care. I am a big believer in the use of the TPM (total productive manufacturing/maintenance) approach as well as use of Lean/Six Sigma programs to improve productivity.
Finally, good and effective communication is probably one of the single greatest needs in a company and not every company does it too well. Companies have to maximize teamwork within their operations, and good communications are vital. Communication needs to be two-directional, (i.e., top-down from management with an opportunity for staff to respond and put forward ideas). I strongly encourage meetings and briefings at the operations level, daily, and weekly. Verbal communication is so important, person-to-person and face-to-face. Email is a very useful tool; however, all too often it is a poor substitute for verbal interpersonal communication; that is a skill we should maintain and develop. People are our principal assets and companies need to put a strong effort into developing people and developing communications and teamwork.
Michael Lacey is plant manager at NIBRT, Fosters Avenue, Mount Merrion, Blackrock, Co. Dublin, Ireland.