Case Study

Implementation Of Single-Use In Drug Substance Filling Before Transportation

By Guy Matthews

PArker

The development of a new product or service is better done as a collaboration between the developer and the potential end user(s). Systems developed in isolation often end up answering questions no one has ever asked, or fail to develop a full solution. With that in mind, this article discusses the product development cycle of a system for bulk filtration of Active Pharmaceutical Ingredients (APIs), how this development progressed from generation one to two and the lessons learned along the way.

Single-Use in Bulk Filling

It is interesting to think that one of the first units of operation to use single-use technology in bioprocessing is the one that has been among the last to benefit from single-use automation. The step in question is the bulk filtration of product prior to shipping. Twenty plus years ago this was already a single-use step; we just did not think of it in that way. Today, in many cases, we are still performing this process in much the same way we did prior to the introduction of single-use technology.

If we go back to the days prior to single-use being widely adopted, the bulk filling step involved a stainless steel tank containing the product being wheeled to a filling suit, then a connection via a steamable valve onto silicone tubing (which would have been autoclaved), through a pump to drive a filtration process.

The critical filling step would then be completed in a laminar flow hood under class 100 (ISO 5) conditions into sterile plastic bottles sat on a balance. The final step to fill the bottle would involve an operator removing the lid and in effect performing an open filling step. With regards to automation, perhaps the pump was operated by use of a foot pedal. Apart from replacing the stainless steel tank with a bag and the steam cross with aseptic connectors, the process as performed today has changed very little.

A customer approached Parker and asked for help in developing a solution that would address a number of concerns related to this unit operation.

Customer Concerns

  1. Eliminating open processing when filling high potency active pharmaceutical ingredients (HPAPI) to protect the operator and the product
  2. Standardizing the filling platform with a view to standard operating procedure (SOP) writing, thereby simplifying training and eliminating
  3. variation from the process.
  4. Reducing the number of people involved directly in the filling step in order to minimize the people in the clean room during a critical operation.

Figure 1: SciLog® SciFlex Filter and Dispense System

In collaboration with the customer, Parker developed the generation one SciLog® SciFlex Filter and Dispense System (see fig. 1) to address all of the above concerns.

The system allowed fully enclosed automated bulk filling of the HPAPI into bottles in preparation for transportation to a filling site. Working with the customer, we were able to identify a number of benefits of automated closed filling.

The Elimination of False Positives Resulting in the Predictable Release of Product

A false positive brings with it an inevitable quarantine and investigation process, all of which takes time. It can be difficult to assign a value to this beyond the cost of completing a deviation investigation and review. In terms of administration costs alone, it has been reported at a starting figure of €2,000, no doubt rising to tens of thousands and beyond if the deviation results in rework being required, or in the most extreme cases, the batch being rejected.

Time Saved Compared to the Manual Process

We were also able to generate data on time savings based on two filling volumes and a set batch size. If these savings were applied to a facility producing 35 batches per year, the time saving and, therefore, cost reduction would be hundreds of thousands of Euros.

Table 1: Time required to process a 20 L batch based on manual or automated filling

Standardization Drives Simplification

With a standard platform training and SOP writing become simpler. As a result, operators perform the task to consistent standards reducing deviations and the risk of operator error. The consumables used in the process are standardized and, as a result, simplify the supply chain and handling process, again reducing the risk of operator error.

At this stage in the product life cycle, Parker was able to provide a solution that put liquid into bottles on a standardized platform using a fully enclosed automated filling process. This became the generation one SciLog® SciFlex Filter and Dispense System.

As a producer of equipment, we thought our responsibility ended at this point. What we learned during conversations with our customer was that putting liquid in bottles was not the end point. What mattered was achieving the required outcome, namely the safe arrival of the bottles at thefilling site. What we had not looked at, but what wasneeded, was what happens to the bottle after it had been filled.

Customer feedback drove the development of generation two (see Fig. 2), but critically, this was not just focused on hardware.

Figure 2: Generation two SciLog® SiPure FD System

Working with the Customer to Identify Improvements

Increase the Filling Accuracy

The filling accuracy on the generation one system was +/- 10%. This was initially deemed to be acceptable as the process was bulk fill. However, feedback from the Quality Assurance team at the customer site lead us to increase the filling accuracy to a much higher level of +/- 10 mg in 1000 mg. What drove this was the knowledge of how many bottles they needed to fill as well as product and consumable reconciliation.

In the generation one system, the filling accuracy was based on a load cell reading off the skid. In the generation two system, the load cell is located under the receiving vessel. With the generation one system, based on a 20L and a 500ml fill, there could be anywhere between 36 and 44 bottles to be filled, all of which need to be prepared and accounted for - either filled bottles or empty discarded bottles. With the improvements in the generation two system, the maximum number of bottles required is 40 while the minimum is 39.

Table 2: Improvement in consumable requirements predictability linked to filling accuracy

The Improvement of the Filling Process can be Assessed in a Number of Ways

a. Speed of filling: This can be controlled by the end use. What determines the filling speed is the balance between minimizing the production of foam (slower is better), accuracy of fill (slower is better) reducing shear exposure (slower is better) and running the most efficient process (faster is usually better). The generation two system allows for rapid (based on foaming and shear information) fill to 90% of target volume, then the process can be run at a slower rate to ensure accuracy of the fill, thereby balancing the requirement for product quality and process efficiency.

b. Liquid dropped into a bottle vertically from a cap will result in foam: To avoid this, a slow filling rate is required. This foaming cam be mitigated by running the liquid down the side of the bottle, thus allowing for a faster filling rate. To facilitate this, Parker developed a J-tube system which diverts the flow of liquid to the bottle side (Fig. 3).

Figure 3: J-tube design directing the fluid flow to the side of the bottle

Process Facility Knowledge Should Drive Component Selection

Single-use systems can consist of many materials: Platinum cured silicone and or thermoplastic elastomer (TPE) for tubing, polycarbonate or PETG bottles, polypropylene of PVDF fittings to name but a few.

These materials need to work at a specific range of temperatures. For example, bottles may be filled under ambient conditions with the solution being filled coming out of cold storage at say 4oC. This presents little or no challenge from a material compatibility point of view.

However, take those materials and store them in dry ice at -78.5oC and now the choice of material becomes  critical. PETG has a lower temperature specification of -40oC while the polycarbonate specification is -135oC. TPE becomes brittle at around -40oC while silicone retains its elastic properties well below the -78oC seen under dry ice storage.

Knowing the full extent of the storage conditions the product will be subjected to across the supply chain means that materials can be chosen to support the process. However, not all products are compatible with all materials used to construct a single-use assembly.

For example, a protein may bind to platinum cured silicone so it the material cannot be used in the single-use system. In that instance, there may be no choice but to use a TPE tubing. So long as the end user has disclosed the low temperature shipping process, the necessary safeguards around handling and manifold support can be put in place to protect the product.

Validate the System

The SciLog® FD was designed and has been validated to perform the fully automated and contained filtration and dispense of bulk APIs. As a piece of hardware you could consider this validated.

However, the function of the Parker equipment designed is to place liquid into bottles for shipping. There are two parts to this process: the filtration and dispensing of the product followed by the shipping to the final destination. If the shipping cannot be completed successfully, we do not have a solutions, merely part of a solution.

As a result of feedback, Parker completed a shipping study to ASTM D4169 (see table 3).

In addition to the testing, the bottles were subjected to further testing to demonstrate the post shipping integrity of the bottles.

It is only after completing this study that we could claim to have a system for the filtration, dispensing and shipping of bulk APIs.

Table 3: Contents of ASTM D4169 performed using distribution cycle 13 at assurance level II

Conclusion

During product development, unless you are able to collect feedback from a wide range of stakeholders, you run the risk of developing a solution that is either incomplete or, worse still, one that answers a question that has never been asked. It was only by working closely with our partner that Parker was able to identify what truly mattered in this process beyond the functionality of the system.

  • Filling accuracy to support process predictability and consumable use
  • Delivery of liquid to the bottle to optimize the process time
  • Elimination of foaming
  • The importance of understanding the full supply chain conditions and the impact that it has on material selection
  • Understanding what the true outcome is - in this case not just putting liquid into bottles, but the safe arrival of those bottles at the fill finish facility

Taking all of these factors into account drove the development of the SciLog® FD hardware and the validation package that supports the whole process. It was by doing this that we were able to bring all the advantages of single-use technology and single-use automation to bear on this critical step to privide a solution that was focused on the required outcomes.

About the Author

Guy Matthews has worked in the biopharm industry for the last 20 years starting his career as a scientist at a well-known CMO in the UK before moving to more commercial roles. During this time he has been involved in many projects implementing single-use technology in both upstream and downstream bioprocessing.

Guy now works as market development manager (life sciences) for Parker Bioscience Filtration where he is focused on bringing Parker’s expertise in motion and control to bioprocessing to create robust solutions in single-use technology that enable customers to improve the quality and accessibility of biopharmaceuticals.

Part of Parker Hannifin Corporation, Parker Bioscience Filtration brings motion and control to bioprocessing with high-purity solutions that speed up development times, increase efficiency and safety, and enable reproducible product quality. Incorporating the SciLog® and domnick hunter brands, Parker Bioscience Filtration combines filtration, fluid handling systems and sensors into scalable automated single-use solutions for a wide range of bioprocessing applications. Visit www.parker.com/bioscience to find out how Parker can create your single-use solution.