I talked with NNE Pharmaplan’s Kim Vincent Andersen (single-use technology and biotechnology specialist) and Niels Guldager (global technology partner in biotech) to discuss their experiences with client facilities that incorporate significant elements of single-use technology. In particular, they highlighted a recent project for Novo Nordisk involving a large-scale greenfield filling and inspection facility in Hillerød, Denmark. Find more detailed information about the project online at https://goo.gl/yp4LQh. And you can watch a video about it here: https://youtu.be/czwwgdt3CxI.
A Case Study
You are leading the design of a fill–finish facility that applies single-use technology in critical process steps. Can you describe the project and its application of disposables?
Andersen: The facility is a US$300 million, 10,000-m2 insulin filling facility currently under construction by Novo Nordisk in Denmark. It will produce commercial supply of insulin products for the global market.
Guldager: We are working closely with our client’s end users and subject-matter experts (SMEs) on formulation and filling technologies to determine the optimal single-use system (SUS) designs. Some equipment will be stainless steel, so in reality it is a good example of a hybrid facility.
Disposables for Fill–Finish
Why are manufacturers applying single-use technology in fill–finish operations?
Andersen: SUSs are gaining momentum in fill and finish for a number of reasons. In many cases, there will be an attractive business case: Eliminating clean-in-place/steam-in-place (CIP/SIP) operations leads to shorter batch change-over times, thus increasing capacity. Of course, you save a lot of work, effort, media, energy, and waste when you don’t need to build for and perform CIP/SIP and validation thereof.
When it comes to regulatory concerns, SUSs are an efficient means to mitigate risks such as contamination. In multiproduct facilities, you also gain a lot on flexibility. This was important to Novo Nordisk because apart from an array of insulin products, the plant also will be used for new-product entry.
You gain flexibility: It is faster and less complex to change between products because cross-contamination is virtually eliminated. You worry less about cleaning and cleaning validation and presenting data proving no risk of cross-contamination. For hybrid systems such as Novo Nordisk’s, advantages are of course less extreme. For high-potency facilities, there is also the benefit of enhanced containment and operator safety from using closed SUSs and closed connections (sterile connectors).
Guldager: The more you move toward 100% single use, the greater the upsides will be with regard to potential upsides in reduction of installed equipment, floor area, and housekeeping activities are significant. At this scale of filling operations, traditional technology would require a large number of 1,000-L mobile tanks in constant circulation between different process states: in-process, after process, rinsed, in service, CIPed, SIPed, and ready for process. Maintaining that flow requires not only monitoring the hygienic state of equipment, but also staging operations that use up significant floor area. Single-use technology reduces the scope of such activities to more simple storage, set-up, and dismantling activities.
Risk Management
How do you handle risks associated with disposables in these critical final processing steps?
Andersen: First, you need to acknowledge that single-use technology is fundamentally different from traditional systems, so your quality set-up needs to adapt to this. There are indeed risks, and you need to identify and address them over the entire lifecycle of your SUS.
Some risks are associated with the supply chain. Familiarizing your organization with supplier activities — identifying and addressing associated risks — will be new to many companies. Supply chain management requires quite some effort and a structured approach. Close cooperation with suppliers is recommended highly, and we have had some very good experiences and open dialogs. It is of mutual benefit to share learnings, of course.
In approaching SUSs in fill–finish, it is key to perform risk assessments with an increasing level of detail as you progress in your design. Compared with traditional systems, mitigations often need to be supported by an array of practical tests (e.g., sterile connectors, tubing, and mock-ups of manual operations). Of course, supply security needs to be carefully looked into by the sourcing organization.
Guldager: In fill–finish, a number of specific risks need special attention because there are no subsequent “mitigating” process steps. Examples include leachables and extractables and particle formation (e.g., from single-use bag surfaces and tubing arrangements). These risks must be evaluated within the array of practical tests. A bracketing approach — grouping together processes based on worst-case scenarios — is useful in considering leachables and extractables for a large number for formulations in the same facility.
Andersen: We also need to highlight the safety aspects. As a principle, single-use technology does bring operators into closer contact with equipment when setting up and dismantling systems. Control of tubing arrangements and single-use bag transportation routes must be well designed. Aerosol formation and operator protection may be necessary for dismantling systems.
A Little Advice
What are your key recommendations for disposables implementation?
Andersen: You need a very structured approach based on science and risk management. Essential elements include practical testing early in the game, close cooperation with suppliers, reference visits to fill–finish manufacturing sites, and cross-industry sharing of experiences.
Guldager: A user-requirements specification (URS) is crucial for success. You need an extremely strong URS concept that will be durable for use all the way through tendering, supplier bid clarifications, and supplier management. That work will serve as a basis for validation. Cross-industry sharing of experience in this project tells us that many drug-product manufactures want to go in this direction because of the high criticality of fill–finish operations and the technology-specific risks involved.
Looking to the Future
Where do you expect future single-use technology development for fill–finish operations?
Andersen: I would mention leak testing and standardization (of requirements architecture and associated test standards as well as batch-release tests and documentation). I expect to see more use of SU mixers and filling manifolds, not just assemblies, tubing, and connectors. Supplier facilities will move to real good manufacturing practice (GMP) compliance from the current GMP-like processes. New facilities approved by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) will pave the way for further implementation as regulatory standpoints become clearer.
Guldager: We are taking part in some early discussions about fully integrated continuous manufacturing, reaching from drug substance all the way to drug product. Although these are early days, we believe that single-use technology has a significant role to play in any future fill–finish manufacturing philosophy.
Cheryl Scott is cofounder and senior technical editor of BioProcess International, PO Box 70, Dexter, OR 97431; 1-646-957-8879; cscott@bioprocessintl.com.