Fuel Monitoring Matters

Although bulk filtration of a product prior to shipping was one of the first bioprocessing steps to benefit from single-use technology, it has been one of the last to benefit from single-use automation.

Indeed, for many biopharmaceutical manufacturers, the process has changed very little from the days before single-use technology was adopted: the main differences have been the replacement of the stainless steel tank with a bag and the steam cross with aseptic connectors. 

Parker Bioscience Filtration was approached by a customer to develop a solution that would address concerns around the bulk filtration unit operation. 

To learn more, download the full white paper: Implementation of Single-Use in Drug Substance Filling Before Transportation

• Protection - As the customer was filling high potency active pharmaceutical ingredients (HPAPIs), it needed to eliminate open processing to protect the operator and the product. 

• Standardization and simplification - The customer needed to standardize the filling platform in order to create a standard operating procedure (SOP); this would simplify training and eliminate process variation.

• Hygiene -The customer wanted to reduce the number of people involved directly in the filling. 

Working closely with the customer, Parker Bioscience Filtration developed the Generation One SciLog® Filter and Dispense System. This enabled fully enclosed automated bulk filling of the HPAPI into bottles in preparation for transportation to a filling site. 

Parker was able to identify several benefits of automated closed filling:

• No more false positives - The elimination of false positives meant that the customer would not be exposed to the costs (and lost time) of the quarantine and investigation process related to a false positive. Nor would it be exposed to the risk of a batch being rejected. 

• Saving time - Comparing manual filling and automated filling, data was generated on time savings based on two filling volumes and a set batch size. If these time savings were applied to a facility producing 35 batches per year, the cost reductions generation could run into €100,000s.

• Reduction in clean room personnel required - As the process is fully enclosed and automated, the need for QC sampling and QA oversight was reduced - this meant fewer staff were required in the clean room. 

• Standardization driving simplification - Training and SOP became simpler as a result of standardization. The risk of deviation and human error was also reduced, and the supply chain and handling process was simplified. 

Although we had developed a solution for a fully enclosed and automated filling process, collaboration with the customer did not stop there. The safe arrival of the bottles at a filling site was the customer's priority - and taking into account their feedback, we developed the generation two SciLog® Filter and Dispense System.

The filling accuracy of the generation one system was +/- 10 percent - initially deemed acceptable.

However, the filling accuracy was increased to a much higher level of +/- 100 mg following feedback from the customer's QA team and our knowledge of how many bottles they needed to fill, as well as product and consumable reconciliation. 

With the generation one system, based on a 20 L and a 500 ml fill, anywhere between 36 and 44 bottles were required. With the generation two system, the maximum number of bottles required is 40 and the minimum is 39. 

As the generation two system allows a rapid fill to 90 percent of target volume, the process can be run at a slower rate to ensure accuracy. This balances the requirement for product quality and process efficiency.

Parker also introduced a J-tube system which diverts the flow of liquid to the side of the bottle. This was developed to prevent the foaming that would occur if liquid was dropped into a bottle vertically. 

It is essential to choose materials that can support the process - and this can only be done if the full extent of the storage conditions is known. A solution may be filled following cold storage at 4°C, for instance, but may then be stored in dry ice at -78.5°C. This will have a critical impact on the choice of materials. In addition, not all products will be compatible with all of the materials used in a single-use assembly. Again, knowledge is key.

While the system was validated to perform the fully automated and contained filtration and dispense of bulk APIs, this was not the end of the validation process. 

Shipping of the product to the final destination was also part of the solution Parker needed to provide for the customer and, therefore, this also needed to be validated. To do this, Parker subjected the bottles to further testing to demonstrate their post-shipping integrity — a crucial final step in validating the entire process.

Our work in developing the generation two SciLog® Filter and Dispense System underlined the importance of truly understanding what matters to a customer — and in this case, that went beyond the system's functionality.

To learn more download the full white paper: Implementation of Single-Use in Drug Substance Filling Before Transportation

This post was contributed by Guy Matthews, division marketing manager, Parker Bioscience Filtration, United Kingdom

Parker Bioscience Filtration specializes in automating and controlling single-use bioprocesses. By integrating sensory and automation technology into a process, a manufacturer can control the fluid more effectively, ensuring the quality of the final product. Visit www.parker.com/bioscience to find out more.

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How to Successfully Scale-Up Automated Single-Use Bioprocesses

Whether you are running a process in a 30,000 L bioreactor in fed-batch mode, a 200 L continuous process, or have scaled-out (rather than up), you will start at small scale and look to increase the volume - scale-up - to some degree.

However, we are recognizing that some biotech companies aren't adopting single-use automated technology until the process reaches pilot scale. This can reduce the likelihood of a successful outcome or the speed of the development process, as process rework may need to be managed further along the manufacturing development process. In some cases, changes to inefficient processes may be more difficult to implement, especially if they have already been approved.

The adage "start with the end in mind" has never been more relevant. For scale-up to be successful, we recommend using the same automated single-use equipment, strategies and materials from the R&D stage through to manufacturing scale. That way, speed to market can be optimized through simplified technology transfer of optimal process. You will also avoid unexpected rework that may come about due to material compatibility or availability issues.

Speed to market is of critical importance, both from a return on investment point of view, but also with the benefits to patients in mind.

Having single-use automated technology in place at the R&D stage can make the move into the manufacturing stage more efficient.

The benefits include:

• Materials are pre-qualified at the R&D stage and approved for use in the application.
• Vendors are pre-qualified, audited and already in the supply chain.
• Operator training time is reduced.
• User confidence with the technology is increased.
• Using scalable automation solution and single-use components increases the likelihood that control parameters developed on a smaller scale system are available on a larger system.

And, if you use single-use technology during R&D you can also benefit from:

• Decreased turnaround times - as components don't require cleaning or regeneration.
• More consistent results - from using pre-made disposable manifolds, rather than building a flow path for each different processing run.

However, there are a few common pitfalls to avoid, which include making incorrect assumptions regarding how processes will behave at larger scale.

Parker Bioscience Filtration is delivering a webinar on November 12th, 2019 which will help biopharmaceutical manufacturers build a strategy for effective scale-up of filtration and single-use processes that will facilitate technology transfer, in order to avoid delays in commercialization caused by inconsistent scale-up of a single-use process between R&D and manufacturing.

It will explain how to conduct a small-scale filtration trial using an automated single-use system at laboratory scale and examine the advantages this provides.

The webinar will also further explore the benefits of single-use technology in both R&D and manufacturing, and consider how to ensure successful implementation of single-use automation from laboratory scale through to large-scale production.

Register now for our webinar: Ensuring Successful Scale-Up in Bioprocessing

This post was contributed by David Heaney, market development manager (life sciences), Parker Bioscience Filtration, United Kingdom.

Parker Bioscience Filtration specializes in automating and controlling single-use bioprocesses. By integrating sensory and automation technology into a process, a manufacturer can control the fluid more effectively, ensuring the quality of the final product. Visit www.parker.com/bioscience to find out more.

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Protecting Your Bioprocess From the Risk of Human Error

How to Successfully Scale-Up Automated Single-Use Bioprocesses

Automating and Enclosing Bulk Fill Operations - the Way Forward?

Single-use solutions have been widely adopted on a global scale within the biopharmaceutical industry due to the many advantages and process improvements they offer.

Key applications for single-use assemblies include the creation of process fluid flow paths, buffer/product storage solutions and sampling systems on varying scales. 

Most of these systems will start with either a bioprocess container or a tubing option and require the ability to connect to further pieces of equipment or additional single-use systems/manifolds.

In order to achieve this connectability, some form of connection needs to be selected — but with so many different connection types available, where should biopharmaceutical manufacturers start?

There are many different options available when embarking on the selection process. Consideration must be given to whether the connection type needs to be aseptic to provide quick and easy sterile connections, (even in non-sterile environments) or non-aseptic (to provide quick and easy non-sterile connections).

The choice should be guided by the process itself — and the capability of the manufacturing plant should also be taken into account. 

Key factors which will determine the correct choice of connection type include:

• Whether the connection is to be made inside or outside of a laminar airflow hood.
• Whether the connection needs to address any specific safety requirements.
• Process conditions and compatibility.
• Bioburden control.
• Experience of operatives.
• Suitability for purpose.

Only when these factors have been addressed can the end-user begin to fully specify the connection type required. 

The Luer connector is the simplest connector. It consists of both a male and female form, and the connection is made using a twist-lock action. These connections are suited to sample lines (with syringe connectivity) and low flow narrow-bore tubing applications and can be used within a laminar airflow hood to create aseptic connections.

However, there is a downside: potential misconnections can occur when they are not mated correctly. 

Quick connectors such as the MPC, MPX or MPU from CPC (Colder Products Company) are similar to Luer connectors in that they can be used within a laminar airflow hood to create aseptic connections. They have the added security of a push-fit feature with a secure locking mechanism. 

Triclamp (sanitary style) fittings can be used as connectors. While these are effective and secure connections, care must be taken to position the required o-ring seal within the connection prior to fixing the connection using an external clamp. The sheer size of the external clamp may make this an unsuitable method for connecting narrow bore or thin-walled tubing due to the weights involved and the potential for kinking/doubling of the attached tubing. Triclamp connections can be used within a laminar airflow hood to create aseptic connections. 

Should aseptic connections be required to be made outside of a laminar airflow hood, two options are available, which both allow the connection of varying tube sizes:

The first option for connecting aseptically in a non-aseptic environment would be to use a gendered aseptic connector, such as CPC AseptiQuik® gendered, which has both a male and female version. The benefit of using a gendered connection is that it can help by safeguarding which lines can be connected to certain points in the process; this helps to mitigate against human error and the accidental connection of the incorrect lines/equipment.

When designing single-use assemblies using a gendered connector approach, care must be taken to ensure that the correct male / female side is designed into each part; this in itself can also create some areas for error to creep in. 

Should the end-user not have any concerns over an accidental connection to the incorrect lines/equipment, or simply want to remove the error of male/female connector type which can creep in during design, there is the genderless aseptic connector, such as CPC AseptiQuik® genderless. These connectors take out the requirement for designing in the correct male/female orientation and can enable universal assemblies to be manufactured and connected with many other assembly/equipment types. 

Both gendered aseptic connectors and genderless aseptic connectors operate via a mechanism that enables connection in non-sterile environments to be made possible. This is because of the use of proprietary seals which mate together before a protective seal is removed, thus keeping the process stream in its aseptic/sterile condition. 

Should sterile connections between traditional stainless steel biopharmaceutical processing equipment and single-use assemblies be required, there is another option:

Steam to connectors, such as CPC Steam-Thru®, work by allowing steam to pass through the section connected to the stainless steel equipment. Once steamed and connected, a valve within the connector is manipulated, creating a sterile or aseptic flow path. 

It is apparent that there are many connections capable of creating or maintaining an aseptic/sterile environment, but without the correct process condition assessment, operator care or design considerations, biopharmaceutical manufacturers could be looking at a costly connection failure. 

Download our white paper to find solutions to more single-use challenges: Single-Use Technology: The Next 5 Challenges to Conquer

This post was contributed by Graeme Proctor, product manager (single-use technologies), Parker Bioscience Filtration, United Kingdom.

Parker Bioscience Filtration specializes in automating and controlling single-use bioprocesses. By integrating sensory and automation technology into a process, a manufacturer can control the fluid more effectively, ensuring the quality of the final product. Visit www.parker.com/bioscience to find out more. 

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