In parenteral manufacturing, management of the material volumes of high-value, low-volume biologic drug products, such as those based on antibodies and plasmids, is critical during all phases of the production process. Minimizing volume losses is critical to ensuring the lowest production costs possible. Fill–finish operations, in particular, present several opportunities for product losses. Careful handling of product throughout the compounding, filtering, and filling stages can, however, eliminate many major sources of product losses, according to Jenny Ekegren, technical sales manager with Cobra Biologics, a contract manufacturer providing aseptic manufacturing. The company recently initiated a project to modify its fill–finish operations with the aim of minimizing product losses, and succeeded in achieving a more than 10-fold decrease in product waste. Ekegren and Mattias Nordlander, a process engineer with Cobra Biologics, spoke with Cynthia Challener, editor of the Pharmaceutical Sciences, Manufacturing & Marketplace Report, about the project.
Pharmaceutical Sciences, Manufacturing & Marketplace Report: Was there a particular incident or event that led to the evaluation of the fill–finish process?
Ekegren (Cobra Biologics): The need to evaluate product losses actually developed quite naturally. Prior to 2011 when Cobra Biologics acquired the fill–finish operations from UniTech, we were largely involved with the filling of large-volume, lower-value active pharmaceutical ingredients (APIs). Cobra, however, focuses on high-value, low-volume products, and therefore we needed to adapt our operations to maximize the efficiency of the production of these types of APIs, which in part meant minimizing as much as possible any product losses during fill–finish operations.
Pharmaceutical Sciences, Manufacturing & Marketplace Report: What were the initial goals of the project?
Ekegren (Cobra Biologics): We set out from the beginning to reduce our product losses without making any changes to the process and without any capital investment. Importantly, we were able to achieve that goal and find ways to significantly reduce product waste without making any significant financial investments. As a result, the project was a very successful, low-cost, high-reward endeavor.
Pharmaceutical Sciences, Manufacturing & Marketplace Report: How did you conduct the mapping of the process? What tools/approaches did you use? What did the process involve?
Nordlander (Cobra Biologics): Our mapping effort was not a formal one, but relied on the extensive expertise in biologics and parenteral manufacturing that we have at Cobra. First, we did break the operations into two stages–compound and filtration in one stage, and filling in the other. Then, we basically brought everyone together, considered all of the aspects of our fill–finish operations and did some brainstorming. The result of these efforts was the identification of all of the potential sources of losses. Next, the potential impact of each of the sources was considered, and those with the greatest potential were prioritized. After that, we began developing solutions that would address the identified problem areas.
Pharmaceutical Sciences, Manufacturing & Marketplace Report: What did you identify as the major causes/sources of losses in your small volume fill–finish operations?
Nordlander (Cobra Biologics): Two major changes brought about the biggest improvements: minimizing the material left in tubing and a new filter flushing protocol.
Our fill–finish operations are based on completely disposable, single-use systems. What we found was that we were losing a considerable amount of liquid in the feed and empty lines used in the compounding process. By optimizing the system to minimize the amount of material left in this tubing, we were able to nearly eliminate waste in this part of the process. This change was really a material-handling issue and involved determining the best positioning of the bags and tubing. In fact, the pumps we use are very accurate, and if the working procedures and disposable fluid flow paths are optimized, it is possible get most of the product out of them.
With respect to the filter, it was a matter of changing the flushing procedure. In the past, when we worked with low-cost APIs, we flushed the filter with the product and that material went to waste. Doing so with high-value APIs is not practical. Therefore, we now flush the filter with an appropriate buffer solution, thus completely eliminating the product waste from this step.
Ekegren (Cobra Biologics): Other changes were made that made incremental improvements. For example, for our large-volume filling processes, we always used two needles. For low-volume products, however, it isn’t necessary, and eliminating one needle reduces the product losses in this operation by half. We also switched to smaller compounding and filling bags in order to reduce the contact area for the product.
All together, the changes that we made have helped us maximize the product yield for our customers. Today, our product losses for a typical fill–finish operation are less than 0.1 liter.
Pharmaceutical Sciences, Manufacturing & Marketplace Report: What further efforts are underway?
Ekegren (Cobra Biologics): Our ongoing efforts to minimize product losses will be focused on product sampling. We believe there is room to reduce product losses due to sampling. In particular, we are looking at the samples required, for example, for bioburden determination. A significant quantity of material is used for these analyses as much as up to 10% of a product batch just for bioburden testing alone. We are optimistic that we can reduce our losses to some degree while still remaining in compliance with all relevant regulations.