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For certain APIs, including semi-synthetic antibiotics, continuous filtration and drying improves productivity and quality.
Continuous processes for production of antibiotics, including downstream filtration and drying processes, can improve both productivity and quality, says Detlef Steidl, senior sales director of process technology at BHS-Sonthofen, which manufactures filtration and drying equipment. Steidl notes that the company has seen successful transitions from batch filters (including agitated Nutsche filters as well as centrifuges) to rotary pressure filters. Pharmaceutical Technology spoke with Steidl about some of the benefits and challenges of moving to continuous processing.
PharmTech: What do you see as the trends in continuous production of pharmaceuticals, particularly for antibiotics?
Steidl (BHS-Sonthofen): As pharmaceutical companies move their production from traditional batch to continuous manufacturing processes, they benefit from higher throughput, significant savings, and greater yield. Particularly in the production of antibiotics, we often see that manufacturers reach the limits of their existing production processes when they want to increase their capacities. We have seen cases where the introduction of continuous filtration and drying processes increased production in the order of 150%, with a fraction of the investment costs of the previous [batch] manufacturing process.
Semi-synthetic antibiotics traditionally meet the conditions for continuous processing. These products are high in demand, have an average filtration rate, and they are relatively fast to dry. Because they are sensitive to strong forces, they benefit from the gentle treatment in continuous dryers.
PharmTech: What are the limitations or challenges in filtration/drying that need to be addressed to allow continuous production to occur?
Steidl (BHS-Sonthofen): Product characteristics must meet continuous requirements. In addition, the demand of the product must be high enough to make continuous production economically attractive. If only a few kilograms of a certain API are required per year, then investing into a continuous process is not economical. At least for a couple of months [of a year], the continuous process should be in use, preferably 24/7.
Furthermore, product behavior during filtration and drying must allow for rapid processing. In filtration, the product must build a filter cake in usable height (3–5 mm) within seconds or a maximum of three minutes. The same is true for drying. The drying process should not take too long to allow for a continuous process to be set up. Product behavior should also be stable, within a limited range of fluctuations. This [stability] can be achieved more easily in fully continuous processes.
A fully continuous process from reaction and separation to drying is preferred; it allows the reactor to be operated continuously if possible. If fully continuous is not feasible, then switching from reactor A to B and back requires detailed analysis and good engineering controls. However, if the reaction is batchwise, but several batches are alternately fed into the downstream process, then a ‘semi-continuous’ process [with continuous downstream processing] still makes a lot of sense.
In some cases, manufacturers still stick to batch dryers because the drying time is quite long, the operation requires very low vacuum, and overall capacity is not too big. Here, filtration takes place over a period of six to 12 hours until the dryer is full. The filtration process is then stopped until the dryer has done its job for a couple of hours, allowing the process to benefit from the continuous thin cake filtration with an alternating (on/off) operation.
PharmTech: What are the equipment differences for filtration and for drying that are different for continuous vs batch?
Steidl (BHS-Sonthofen): In traditional batch production, each production step involves an autonomous batch process. The overall production batch is produced in independent steps and sequences. A typical batch filtration technique is Nutsche filtration, which may use pressure or vacuum in a closed vessel. The subsequent separation and cleaning in the Nutsche filter require several manual actions, such as taking samples, analyzing them in the lab, and switching the washing method. Some amount of active ingredient is lost in the Nutsche filter, caused by the turbid flow stage at the beginning of filtration and remainder at discharge.
A fully continuous separator, such as the rotary pressure filter, has a smaller filter surface. The equipment reduces cake thickness, which results in lower cake resistance. Thus, the filtration pressure can be lowered, which allows the process to be optimized to ensure high performance over the long term. Another major difference is that online monitoring allows the operator to quickly optimize the quantity of washing agent.
A consequence of the nature of continuous processing is that the quality parameters will always be within certain limits and be constantly monitored. Quality control is carried out reliably for the entire production, compared to batch operations that rely on sampling methods with the corresponding risks.