Vice President of Sales and Marketing
The pharmaceutical industry is by definition highly innovative. New therapies are constantly being developed that treat diseases via novel mechanisms of action. Not surprisingly, though, innovation has lagged somewhat when it comes to drug manufacturing. The production of biologic and small-molecule medicines involves highly complex, multi-step processes, and ensuring the safety of every formulated drug product that is delivered to a patient is a top priority for pharmaceutical companies and regulatory agencies. New technologies must be carefully and extensively evaluated to confirm that they do not have a negative impact on drug performance (safety and efficacy). Early adopters of innovative approaches to manufacturing assume a high level of risk, but do have the potential to reap significant rewards. As one of the earliest contract manufacturing organizations (CMOs) in the pharmaceutical industry to implement automated production for batch manufacturing operations, Fermion has been benefiting from more robust processes, increased worker safety, reduced labor costs, and shorter production times, all of which have given the company the ability a measurable competitive advantage.
More Than Just Cost Savings
In the pharmaceutical industry, automation of manufacturing processes must be completed while maintaining the highest safety standards required by regulatory agencies, which apply to both equipment and software. If done right, however, the implementation of automated processing solutions can actually improve the quality consistency of products, increase operating productivity, and add flexibility. The result: more cost-effective and efficient manufacturing systems that allow safer drugs to reach the market more quickly.
To most effectively automate a pharmaceutical manufacturing process, it is necessary to first thoroughly understand the process. Such a high level of process understanding is not common in most manufacturing facilities, so gaining such knowledge in itself is beneficial to the company. All aspects of the process must therefore be evaluated – the overall process design, equipment types and specifications, required operator actions, and process conditions (temperature, pressure, order of reagent addition, stirring speed, need for cooling, etc.). This information is used to identify key areas for both control and optimization of the process through automation.
At its basic level, process automation can lead to a reduction in the number of operators required to run a given process. At the same time, minimizing operator interaction reduces opportunities for human error and process contamination and increases worker safety. Processes consistently operating under optimum conditions provide higher-quality product more consistently, often in higher yields. They also consume less energy, produce less waste and fewer emissions; reducing problems that require shutdown. Clean-in-place (CIP) and sterilize-in-place (SIP) capabilities for most automated equipment reduce downtime between runs. As a result, productivity and efficiency, as well as product quality and process throughput, are improved, while the overall costs and environmental impact are reduced.
However, process automation is only one aspect of most automation initiatives being pursued today in the pharmaceutical industry. Batch and recipe management, facility automation, including integration of production scheduling and purchasing operations: collaborative production management (CPM), and process analytical technology (PAT) are now key components of many automated production facilities.
The digital aspects of automation provide an additional level of benefits, particularly if the control systems are linked with other aspects of plant operation as part of the Industrial Internet of Things (IIoT). In such a scenario, remote access for monitoring of processes is possible. Data from processes in multi-step synthesis of pharmaceutical intermediates and active pharmaceutical ingredients (APIs) can also be linked together for more efficient overall operation. Faster identification and response to process excursions is also possible, and digitally recorded data is easier to manage and analyze for trends. Integration of simulation and modeling tools allows optimization as process conditions change to meet changing market demands. Serialization requirements can be met and data that will be required for FDA’s proposed Quality Metrics program more easily collected when automated systems with digital recordkeeping capabilities are employed.
Real Commitment Required
All of the benefits described above can only be realized, however, if automation is implemented in an effective manner. Not surprisingly, automation of complex pharmaceutical manufacturing and other business processes is not a simple task. First and foremost, all aspects of an automation system, including equipment and software, must meet stringent regulatory requirements. Even computer systems must be validated for their specific intended application. Selection of the ideal automation system (system architecture) for a given process is therefore required early on in an automation program. The use of standards-based hardware and software is also highly recommended.
Effective management of automation projects is also a key factor in achieving a successful outcome. There are many phases of an automation initiative; comprehensive evaluation of the process is only the start. Once sufficient process knowledge is in hand, a project plan should be developed that outlines each step with appropriate deadlines for completion. Design of the automation system, configuration of the hardware and software, and ultimately commissioning and operation of the automated system must be carefully managed to ensure completely and timely execution.
Once installed, automation systems must also be maintained. Often companies retain original systems and slowly add other, newer systems, sometimes from different vendors, ending up with a mixture of outdated and newer equipment, hardware, and software that do not communicate well with one another. Upgrading such systems can be quite challenging. A more effective approach is to recognize from the beginning that all components of a process automation system will require upgrading on a regular basis. The use of standard software and hardware for all aspects of the system, as well as communication protocols that are common for the pharmaceutical industry goes a long way to alleviating many of these issues.
Fermion’s Approach to Automation
Formed in 1970 as a 50-50 joint venture between Rikkihappo Oy (now Kemira Oy) and Orion, Fermion produces generic APIs, intermediates, and active ingredients for both Orion and external customers at its facilities in Finland, which have been FDA inspected and approved since 1979. We serve as a strategic partner to innovative pharmaceutical companies and focus on providing cost-efficient, well-engineered synthesis, process development and life-cycle management solutions. To date, Fermion has commercialized or is awaiting approval of a total of 10 innovative APIs.
To improve its production capabilities, Fermion first began implementing its holistic use of automation in 1985 at its Hanko site, adapting technology used by the Finnish pulp and paper industry for continuous processing. While this benchmark was taken from a completely different industry, the systems used in pulp and paper mills in Finland were the state-of-the-art for the industry. An experienced supplier of automation technology to the paper industry–Altim Control of the Ahlström group (later acquired by Honeywell)–was selected for engineering of those first automation systems. Honeywell continues to be the supplier of the major components of the automation systems used today by Fermion in both of its production facilities.
The overall automation solution at Fermion consists of process management and process modules from Honeywell: the Uniformance® Process History Database (PHD) for plant process data collection and manipulation and the TotalPlant® Alcont automation system for process control. Each system is tailor-made for the specific process involved and configured according to the requirements of CFR (Code of Federal Regulations) Part 11 as established by the US Food and Drug Administration (FDA) (validated according to FDA standards). In addition, the automation systems are upgraded regularly, including improvements in software, equipment, and related technologies.
The process management system contains electronic recipes, batch records, and a database for collecting process data, which can then be easily accessed, searched, and analyzed. Because the historical process data is maintained in the database and is traceable, it can be used for process optimization, troubleshooting, and deviation investigation. For instance, it is possible to compare data for different batches at certain process phases and trace possible causes of deviations in process parameters or product quality, even to the detailed level of the position of a certain valve at a particular time. In addition, the process management system is integrated with Fermion’s SAP R/3 enterprise resource planning (ERP) software, which is utilized for production planning and inventory management.
The process modules consist of instruments and components incorporated into the process equipment. With these automation systems, for example, different valves are adjusted automatically to control the temperature of a reaction based on directions stored in the Uniformance software within the process module. At Fermion, all of the reactors, centrifuges, dryers and final handling equipment are included in the plant-wide automation system. See Figure 1 for a schematic of a reactor automation set-up. Also special utilities, including our VOCincineration plant and heating and cooling systems, are automated.
Figure 1. Schematic of the automation set-up for a reactor at Fermion’s Hanko facility.Measurable Benefits
Implementation of automation systems has provided measurable benefits for Fermion. Of three units at the Hanko plant, semiautomated Unit 1 requires 5-6 operators, while fully automated Unit 3 only requires 2-3–a 50% reduction in operator labor. Company-wide, the introduction of automated equipment has reduced the need for manual labor overall by approximately 15-20%, which has increased operator safety and decreased opportunities for human error. In addition, the quality of products produced using Unit 3 is more robust, and the need for reprocessing has been reduced by a third.
PAT is also employed, allowing careful monitoring and control of process parameters (e.g. particle form and shape) for highly consistent product properties (e.g. particle shape and size for solids) and quality from batch to batch. Figure 2 presents a representative printout for a crystallization process. By using automation, it is possible to consistently use a logarithmic temperature profile in a cooling crystallization. The temperature of the reactor jacket and the reaction mixture are shown as a function of time. The changes in temperature of the reactor jacket and mixture clearly reflect the phases of the crystallization.
Figure 2. Representative printout of reactor jacket and reaction mixture temperatures as a function of time for a crystallization process.Even for semi-automated processes, production times are shorter and the cost of goods sold is reduced. Access to detailed electronic reports and the ability to readily perform graphic analyses enables the evaluation of test runs and efficient process optimization. Furthermore, connecting the process and resource management systems has led to optimization of the supply chain using real-time data on raw material demand and consumption levels. Automation has also enabled Fermion to increase its production volumes significantly.
Conclusion
Most European CMOs that have implemented process automation solutions have focused only on automating the functions related to the actual processes. Recipe management and reporting remain manual tasks, and no central data management system is employed. As a result, integration of separate processes with each other and with other business processes is not possible, preventing these companies from fully realizing all of the potential offered by comprehensive process automation systems.
At Fermion, we have taken a holistic approach to process automation, integrating automated process operations with both data collection and our ERP system. In addition to significant cost and labor savings, increased productivity and worker safety, and minimization of waste, this solution has allowed us to bring process optimization, troubleshooting, and deviation investigation activities to a more advanced level–all of which when taken together has proven to equal real competitive advantage in the eyes of our customers.