Using single-use systems for investigational medicinal product manufacturing has its advantages and disadvantages.
Using single-use systems for investigational medicinal product (IMP) manufacturing has its advantages and disadvantages. Some key advantages are that process implementation is straight forward, particularly if you stay with a supplier’s standard offering, and there can be a reduced facility footprint as well as significant implementation time savings compared with multiple‑use systems. Single‑use systems can increase flexibility and productivity, make it easier to avoid cross contamination and also negate the need for costly steam‑in‑place or clean‑in‑place validation.
Stephen Brown. Chief Technical Officer at Vivalis.
The disadvantages are that technology assessment and the choice of systems for implementation can be complex, and implementation time can be particularly long for personalised systems. Additionally, depending on scale, single‑use systems can sometimes be expensive to implement. Connector and bag integrity is also sometimes a worry and, finally, waste disposal can be more or less complex depending on your location and needs.
With regards to cost management, the implications of implementing single‑use systems depends on many things, such as your company size, your product, the process knowledge to implement and the process validation status. Is your company a large established firm, a biotech start‑up or a CMO? What are your user requirements? Who are the stakeholders? Are you taking a QbD approach from the outset? Depending on circumstances, if you have an existing facility and qualified installations and equipment, for example, you may not see an immediate requirement for single‑use systems in the same way as a company that is just setting up. A more established company might be cost conscious and seek to lever existing installations, or may apply a mixed single‑use/multiple‑use implementation strategy. A new company, on the other hand, may see single-use systems as a faster, more cost‑effective route to arrival in the clinic. Implementation can be faster and the investment outlay for renovation and/or greenfield setup should be less using single‑use systems. There have been some interesting case studies presented that illustrate these points.1,2 Acknowledging these points, I nevertheless draw the reader’s attention to my personal experience that some single-use suppliers can be expensive for this material.
Waste management is an important part of single-use systems implementation — such systems generate more solid waste than multiple‑use systems (which inversely use more process water). Your single-use system implementation plan should lever multiple points here regarding biosafety concerns (product containment); environmental issues (how is your carbon footprint?); collection and storage of wastes and their inactivation before leaving the facility or site; transport and final elimination; and regulatory requirements — although this last point can be somewhat variable depending on your economic area location. The Bioprocess Systems Alliance has published a guideline on this and other subjects related to Single-Use Systems.3
Some people believe that clients seeking to outsource IMP manufacture look more favourably upon companies that use single‑use systems. Is this true? Well, maybe, maybe not.
It’s the old argument about quality, time and money; it depends on the user requirements and where you are in the process validation lifecycle. Think of it from the aspect of it being your money and not that of the outsourcing provider in question. You’re not sure what the future holds or what results you will get and so you will want to move ahead cautiously. You will be looking for the best deal in terms of time and money, and having the appropriate level of quality. In that context, you might be satisfied with a deal from an outsourcing provider with established installations based on multiple-use systems. On the other hand, for some companies, single‑use systems may be seen as being or thinking smarter as they are faster to implement (less to worry about) and less risky from a process perspective.
Single-use systems are of interest to producers of monoclonal antibodies because of the flexibility they bring to manufacturing operations (just to give one example). However, the size limitation for a plastic vessel (1–3 m3) can imply a change of process strategy away from fewer, larger steel bioreactors towards "farms" of single use bioreactors (multiple single use bioreactors of 1 M3). Single-use systems may be particularly attractive, for example, for a company implementing a project handling infectious agents, such as live vaccines or Advanced Therapy Medicinal Products (gene vectors or Cell-Based Medicinal Products) or potent compounds because of the flexibility, easier control of cross contamination and the more efficient use of available facility space. However, where are you in the process validation lifecycle? I just gave a perspective from an early clinical development viewpoint. If you are further along the process validation lifecycle and want to outsource your IMP manufacturing then other issues will have greater weight, such as the level of GMP compliance and the final production scale or process strategy.
The key factors that will influence a small company’s decision as to whether to use single‑use systems or not will be:
When evaluating suppliers and making the correct choice of systems, ‘local’ factors will also play an important role. For instance, supplier strategy; depending on your supplier and technical choice you may be locked into certain technologies and perhaps just one supplier, which means you will not be able to execute a dual supplier strategy. Supplier capacity assessment and the warehousing space required is also important to consider when using single-use systems, as well as a supplier’s after‑sales service and support. Equally, be ready to decide what to do if, as a small company with a critical eye on strategic planning and business opportunities, you have to change your implementation planning. How will your supplier react? Make sure you have read the general terms and conditions of your supplier(s) and be prepared to negotiate on this point and modify it if necessary. These are often old, generic texts, but it can be very inconvenient if the first time you check them out is when there’s a problem!
Depending on the size and value of the project, a technical agreement can clarify the functional aspects of a business relationship. This should not be confused with a commercial agreement (if applicable). The technical agreement will detail the responsibilities (production, quality and regulatory etc.) of personnel within each company as appropriate, and should improve communication and prevent ambiguous situations. You may choose not to implement this type of agreement if the project is minor; however, on the other hand, I recommend this for scenarios with large repeated supplies such as bioreactor bags because of the value of the agreement and quality issues involved.
The application of the above factors can be seen as a risk management strategy,4 indeed, the industry recognises this as the most cost‑effective route to use today and it will also most likely save you time too. This is what many companies have been doing for years, but which has become more formalised with the general adoption and roll-out of Quality Risk Management (QRM) by regulatory authorities. Implementing an appropriate QRM programme during single-use system implementation offers benefits as a means of assessing, controlling, communicating and reviewing risk. The risk assessment process should be applied over the lifecycle of the project. The approach can range from a simple ad-hoc or stand alone application to more robust applications involving qualitative and quantitative methods such as failure modes and effects analysis.
Although in my opinion there are no hard and fast rules, it’s definitely worth small companies implementing single‑use systems. During this process, the company should decide who its stakeholders are and define user requirements, set in place a Project Implementation Plan and as mentioned apply an appropriate level of risk assessment to the whole process.
I’ve given my own personal opinions here based on experience and I advise you to look out for a future technical report from the Parenteral Drug Association on single‑use systems. Prepared by a task force lead by Bob Repetto from Pfizer and Morten Munk from CMC Biologics, this document will definitely help potential new and existing users formulate their ideas coherently and provide the best approach to implementing single use systems.
1. T. Nemes (Novavax), Implementation of Disposables in Biologics Manufacturing (PDA/EBE conference on Biopharmaceutical Development and Manufacturing, Ireland, June 2008).
2. A. Sinclair (Biopharm Services), Sustainability Single-Use Technologies – Environmental Impact and waste Management, (Pharma IQ conference on Disposable Solutions for Biomanufacturing, UK, February 2010).
3. Bioprcess Systems Alliance, Guide to Disposal of Single-Use Bioprocess Systems, http://www.bpsalliance.org/guides.html.
4. S. Brown (Vivalis), A Risk Management Approach to Single Use Systems Selection and Implementation (ISPE conference on Disposable and Containment Technology in Biomanufacturing, France, September 2009).