In light of increasing spending on technology and operations,1 manufacturing for greater efficiency has become a top priority for innovative firms. Operational transparency is essential to product quality and primarily comes from collecting operating data in the most accurate, timely fashion possible.
In order to achieve higher accuracy, the elimination of paper-based methods is a foreseeable goal. Although existing paper-based systems are often validated, they rely on the transcription of manually collected data, which is an increasingly risky strategy. The integration of electronic data collection and documentation — electronic batch records, for instance — within drug manufacturing operations has become a priority. Paperless manufacturing and inventory management systems are in fact quite effective in operation; properly qualified, electronic data capture and management systems can help minimize errors and rework. Digital records are also being integrated with business decision-making applications like SAP® to facilitate plant scheduling and other activities.
In oral solid dose manufacturing, material handling, mixing, blending, compression/tableting and primary and secondary delivery, as well as packaging, are standard operations. Greater process understanding, however, can lead to both increased efficiencies and improved product quality, and ultimately reduced costs. Manufacturers are, therefore, applying process analytical technology to these unit operations, particularly blending, drying and tableting. In process testing and/or monitoring provides real- or near-real-time data and gives operators more in-depth process knowledge, allowing for enhanced process control. Transparency into these processes is one way to achieve the flexibility and cost control manufacturers need.
As OSD formulations have grown more sophisticated, technologies to match these advances have been developed for the manufacture of these novel delivery systems. For example, manufacturers interested in formulating APIs into sublingual thin strips — or using spray drying to create APIs in particle forms suitable for inhalation materials — need access to specialized processing equipment, knowledge and skills. From coating and granulation to spray drying, direct compression and roller compaction, and on to fluid bed and hot-melt extrusion techniques, advanced OSD drug forms require advanced process understanding and control, especially if continuous processes are considered. Interest in these innovative delivery technologies is driven in part by their ability to provide improved solubility and bioavailability, affording greater efficacy while
simultaneously reducing the quantity of API required.
Similarly, there is a focus on reducing physical material handling needs and improving process flow and ergonomics. For example, using different types of containers, such as intermediate bulk containers (IBCs) and flexible intermediate bulk containers, rather than drums, helps with improved process feed/receipt, containment and inventory control, and can reduce waste. The delivery of material right from the warehouse to the processing plant and deploying automatic storage retrieval systems are also beneficial. This is one area where engineering and design firms like CRB can have a significant impact. CRB has experience with systems that not only store in-process material, but also retrieve and mix different materials as needed. As everything is computerized and barcoded, it is possible for operators to know where everything is in real time. Importantly, these systems can be rapidly installed because they are based on available technologies. CRB customers are also implementing direct blend and tablet compression systems, in which the main ingredients are fed directly through gravimetric feeders into an in-line blender and on to a tablet press.
Containing OSD pharmaceutical processes not only assures product quality, it is essential for ensuring operator and environmental safety, especially when manufacturing involves highly potent API formulations. Modular and integrable, flexible isolators and contemporary restricted access barrier containment systems are now replacing open processing operations that were housed in expensive, inflexible clean-room environments.
Equipment manufacturers are developing solutions — from balances to mixer, and blenders to tablet presses — that are designed for use in flexible modular containment systems to meet the growing demand for these capabilities. Where possible, of course, closed equipment and closed transfer are much preferred. Equipment manufacturers are also continually introducing improved systems to meet these needs. For example, high-shear granulating machines now include drying capabilities, allowing two processing steps to be completed in one contained piece of equipment without having to transfer or expose material to the environment. Once dry, the material can be transferred into a blender and then to a tablet press.
Engineering and design firms like CRB, often design customized containment solutions. For instance, we had a request from a customer looking to perform Wurster coating of one-millimeter sugar spheres containing an API with a tri-coating needed for a controlled-release formulation. CRBs engineers designed a containment system that included the fluid bed, vacuum transfer from the fluid bed and closed transfer to IBCs.
The most effective containment solutions, however, are only developed after a thorough risk analysis is performed. While containment is essential to protect workers and the environment from exposure to hazardous substances and to ensure sterility of drug products, there are many unit operations in OSD manufacturing that do not require complete containment. Efficient and cost effective solutions ensure that the right level of containment is provided for each unit operation.
Advances in software are making it possible for engineering and design firms to provide their clients with enhanced services. CRB, for example, uses project management software to carefully track time and effort, allowing any potential scope creep to be identified and addressed early on. Our clients have access to this information, which is integrated across the entire project.
CRB also uses smart process and instrumentation diagrams that can be integrated with instrument data. This information, including instrument data and calibration requirements, for instance, is then accessible to the plant owner, operators and maintenance people.
At the beginning of each project, CRB uses 3D software to show clients different design options. With this software, a client can take a virtual tour of the proposed plant to visualize the equipment layouts, piping and duct work. In essence, the client has an opportunity to see how the facility is going to work before actually being constructed. This tool is very beneficial to both CRB’s engineers and architects and the client, because often it can be difficult to visualize how things will actually flow and function when looking at a flat piece of paper. At CRB we are fortunate to have an extensive library of equipment data provided by many different equipment suppliers that we can incorporate into the 3D software.
For renovation projects, CRB also has partners that can laser scan the space to be modified, including the piping and equipment, and convert this data to drawings. Access to this information facilitates the evaluation of the existing space and the design process, saving clients both time and money, as well as assuring true actual conditions.
More than just space to house equipment, the industry is investing in facilities that are designed comprehensively to promote operator safety, material flow, sustainable quality and cost control for all operations. At CRB, we look at the process first and then build around it, always remaining forward-looking. Our first step is to understand how the process is intended to function. Then we look at whether any hazardous materials or solvents are involved in order to consider containment and utility issues. When this approach is implemented correctly, with process engineers driving many decisions — after considering input from all the relevant disciplines — projecting the potential for expansion is built in. At CRB, therefore, we design cost-effective, manufacturing capability built to sustain efficient flexible operations over the long term
Witold has over 30 years of experience working as a process engineer focusing on pharmaceutical facilities design, related process equipment and supporting infrastructure. Prior to his work at CRB, he had over 11 years of experience in process and project engineering with Novartis Pharmaceuticals (formerly Sandoz).