OR WAIT 15 SECS
Vice President of marketing and disposables implementation at Biopharm Services. She is also the European chair of ISPE's Community of Practice for Disposable Technologies.
How this Big Pharma company successfully implemented disposable technologies in its manufacturing plant.
At the start of this new year, we would like to thank our readers for actively following our column and for your positive feedback through the BioPharm International web site. Feedback is important to us and we encourage you to continue sending it.
Over the last year, several end-users have asked for status update of disposables for a wide variety of final filling applications. The availability of technology in this area has grown rapidly in the last two years. Here we discuss a recent example of a successful end-to-end deployment of single-use technology in aseptic filling. This case study was first presented by Nigel Bell, sterile product lead at GlaxoSmithKline (GSK, Barnard Castle, UK) at IBC's Biopharmaceutical Manufacturing & Development Summit in San Francisco, CA, in December. For this article, Miriam Monge (MM) talked to Nigel Bell (NB) of GSK, along with Ernie Jenness (EJ), a development engineer at Millipore (Billerica, MA), one of the main vendors who actively collaborated with GSK throughout this project.
MM: Nigel, in what context did you start evaluating the use of disposable technologies?
NB: GSK operates two aseptic vial and two syringe facilities, both using fixed and mobile stainless steel systems. These filling systems are not flexible enough to respond to the needs of a fast growing, varied product portfolio. The evaluation of disposables for final filling had already started at GSK, but the acceleration was precipitated by the need to rapidly fill a large quantity of vials for the flu pandemic because we did not have sufficient capacity with the existing setup.
MM: I understand that one factor that motivated you to switch to disposables was that cold fill products challenged the integrity of hard-piped steam-sterilized stainless steel systems.
NB: The thing that puts a lot of strain on the joints in the stainless steel systems is the polytetrafluoroethylene (PTFE) gaskets. These plastics do not have a cold flow memory and so do not react well when being heated to 121 °C for sterilization purposes, then to 5 °C for filling. There have been some problems with leakage over the years.
But even though cold fill products provided the greatest risk from the integrity point of view, there were many other reasons for the need for change. Stainless steel is fine when you are working with one dedicated product, but as we move to filling multiple biopharmaceutical products, the cleaning and sterilization issues rapidly become unwieldy. As the needs of our facility were changing and the regulatory qualification requirements for operations were increasing, it was becoming increasingly challenging to prove that there was no risk of cross contamination.
MM: You talk about the cost and capacity loss through qualification and routine steam-in-place (SIP) as one of the key challenges when working with traditional systems.
NB: When you carry out this analysis, you rapidly realize that the opportunities to improve efficiency, increase productivity, and reduce cost are huge. The time required for cleaning and sterilizing stainless steel; the space and money required for dedicated areas for clean and dirty vessel storage; the downtime required for cleaning, steaming, and product changeover; the massive energy consumption required to generate thousands of liters of water for injection (WFI) to clean and steam equipment, and the cost to make the WFI, are all highly time consuming and offer the potential for efficiency improvement.
Another key concern for us with the traditional systems was the complexity of operation and the associated level of grade A intrusions. With the existing arrangement using restricted access barriers (RABs), the doors between grades A and B would be open taking out and replacing equipment, and so on.
MM: What was the timeline for resolving these issues and implementing disposables?
NB: The project started in June 2009 and we needed to start filling in September 2009.
MM: How was the project managed? What type of team did you put in place?
NB: The new product introduction department set up the URS, working in collaboration with the quality and engineering departments. Nigel Wood, our engineering project manager, played an important part, particularly looking at the integration of the Bosch system, as did our quality assurance (QA) department which took a pragmatic approach to making sound, risk-based decisions. We also worked in close collaboration with the Millipore Mobius experts.
Figure 1. Getinge La Calhene DPTE aseptic transfer system with disposable beta port for transfer of pre-assembled manifold bags assembled with Bosch needles
We carried out a full critical review of all aspects of the filling systems and identified many areas of over complication. We challenged each of these aspects with local QA, then Millipore Mobius expert advisors, and then with the MHRA regulators. We took the approach that every item, regardless of its excellence or complexity, has a failure rate. Thus any reduction in items will have a beneficial effect, and many component parts were removed or at least reduced in complexity.
Other principles were that the product passage from point 1 to 2 should be as simple as possible with as few manipulations as possible (to reduce training and error rates) and wherever practical, as few grade A manipulations as possible. No aseptic connections (including needle assembly) means no SIP to point-of-fill, and minimal grade A intrusions. Our other main motto is, "where there are connections, use the best available."
EJ: Our approach on such a project is to work hand-in-hand with the end-user, a collaborative approach aimed at finding the best overall solution.
MM: How did you evaluate the operational aspects of the technology and the cost of the options? How did you go about risk mitigation?
NB: If it hadn't been for the pandemic, the selection and implementation of disposables would no doubt have taken twice as long. In this situation, convincing the sponsors was somewhat quicker than in a normal situation. QA pragmatism through risk assessment also helped immensely.
One of the key technologies we selected was the Millipore Mobius magnetic drive mixer for bulk drug formulation. We had already done previous testing with this system and found it to work efficiently. The Millipore STS connector was used to secure the sterile connection of the irradiated filter in the grade C environment. In both cases, we went through a series of trials and training, using 10 assemblies for each connection for each process step. It is important that the operators are trained to make the connection, because if you don't make the final click properly it can leak. We chose 50-L bags from Sartorius Stedim Biotech for the bulk drug hold. We selected the Sartorius Stedim bags because we preferred the integrity testing methodology that they have developed. We also carried out a full risk assessment using failure mode effect analysis (FMEA).Other key technologies included the Getinge La Calhene aseptic transfer system, which was premounted with the disposable beta transfer port to allow aseptic transfer of the seven pre-assembled manifold bags mounted with the Bosch needles into the RABs.
Figure 2. Bosch single-use filling needles. GSK's use of Bosch needles began early in the development of the Bosch systems. The Bosch manufacturing process has been improved to control all aspects of quality control, including chemical and microbial levels.
The Millipore team worked to rapidly qualify the assembly of the Bosch needles on the manifold—not a simple task when ensuring the safety of the disposable assembly prepacked with stainless steel needles. The peristaltic pump filling systems from Groninger and Bosch were selected for their high level of accuracy and simplicity. We also work with ready-to-use presterilized stoppers from Helvoet & West Pharma, again eliminating washing requirements.
EJ: Cost was not the primary concern for pandemic flu. Time to get a solution and flow path security and sterility were the primary drivers. For other applications, GSK had a cost target, but was flexible with this as they learned of the operational efficiencies they would gain in using a single-use solution.
MM: Were procurement supply chain issues a consideration?
NB: The pandemic has clearly stretched the global supply of producers and manufacturers. Within our organization, there are strong supply chain management groups with regular reviews and audits of suppliers. We have particularly rigorous controls in place and also exchange a great deal with colleagues in the vaccines division who have many years experience with disposables selection and implementation.
EJ: Our client voiced concern about single sourcing from Millipore. Millipore has met with several clients to review our strategy around this critical area and is taking action such as developing specific bag holder systems that facilitate the deployment of bags from alternate vendors.
MM: What did you see as the biggest challenges with single-use systems?
NB: The fact that we are contracting out the sterility assurance, cleanliness, particulates, and endotoxin control to a third party requires careful auditing and supply agreements. We are of course concerned about the overall system integrity and the perceived weakness of polymeric materials. We were concerned about the reliability of sterile connections in terms of mold variation. Concerning the Bosch needles, we are concerned about ongoing control of the physical, chemical, and micro quality.
MM: One common concern when evaluating disposable technologies for final filling is the question of pre- and post-integrity sterile filter and disposable system testing. How was this handled?
EJ: Pre-use system and filter integrity testing is performed by Millipore. Package validation testing by ISTA 2A drop and vibration and post ISTA package integrity testing demonstrates that the system is integral pre-use.
NB: We then perform pre- and post-filter testing where appropriate.
MM: What do you see as the biggest limitations or risks when working with disposables in the context of final filling operations?
NB: Solvent-containing products are not ideal for disposables because of the potential for evaporative molecular loss through tubing by permeation. We had two preserved multi-dose products that couldn't be filled in a single-use setup.
Having said all of this, I think the best proof of the fact that these systems are a sound solution is that we have now filled 85 million doses and we have had no integrity issues and no sterility failures.
MM: In terms of the benefits, have you been able to measure efficiency and productivity improvements and related cost savings since implementing disposables?
NB: With the disposable setup, the amount of grade A intrusions for the wetted path assembly and strip down has been taken from 2 h to 0 using the Getinge La Calhene grade C to grade A door. This door has a disposable beta door that is premounted with the disposable assembly, and is pre-gamma sterilized and prepared by the vendor with all the relevant documentation. Also, with this arrangement there is no need for the operators to touch the needles, avoiding the need for SIP post-assembly. The system is considerably simplified. The regulators have commented that it could reduce aseptic risk.
The overall time savings are significant. The system preparation time is minimal, the system build time is 30 minutes versus 2 hours for the stainless steel system, sterilization before filling is 0 versus 3.5 hours, operator training time is 2 days versus 2 weeks, SIP qualification is 0 and no six-monthly requalification, the aseptic connections are 0 versus approximately 50 (which were SIP sterilized), and of course there is no cleaning validation. To sum it up, we previously required 36 hours for a campaign fill and we are now down to 12 hours!
In addition, we had a stretch target to reduce energy. Since implementing disposable technologies for final filling, our site energy usage has dropped, significantly reducing our carbon footprint. In addition, we have significantly reduced the carbon footprint and increased capacity by 40%. Validation and routine SIP are key contributing factors, but of course there are many other factors, as outlined earlier. We haven't yet carried out a full cost analysis, but again we expect the overall impact to be significant in terms of less water usage and less chemical usage. And of course the increased capacity means that the number of days gained in manufacturing capacity is huge.
MM: What are the key take home messages you have gained from this project?
NB: Disposables offer a platform-enabling simplification of many activities. The end-to-end solution will provide the biggest benefits, including reducing assembly time, limiting aseptic intrusion, and enabling modular use of set-ups, allowing for minimum hold and maximum flexibility. Consider all connections as highly critical, assume leakage will occur, and build in security. Lastly, control suppliers through quality and supply chain agreements.
All of our forecasts indicate that there is going to be an explosion in the need for vaccines. Previously we were constrained by capacity and now, thanks to disposable platforms, we can rapidly gear up to meet demand.
The track record and experience gained in the use of disposables in a good manufacturing practices (GMP) environment for active pharmaceutical ingredients (API) manufacture has led to an upsurge in interest in recent years in the use of disposable technologies in the fill–finish arena. Recent developments in disposable filling sets for small- and large-scale liquid filling lines, together with disposable rapid transfer port technologies has meant that, for the first time, a disposable fluid path from the formulation vessel to the vial or syringe can be established, thus realizing the full potential of the technology.
The case study confirms that the benefits seen in bulk API manufacture also are realized in the fill–finish facility, specifically with regard to reduced costs, reduced energy usage, and reduced labor.1,2 Based on the outcomes of this case study, the future for disposables use in the final filling arena has significant potential to simplify process operations. This would reduce process risk, significantly reduce carbon footprint, and save considerable time in process operations, notably through reducing the time required for assembly and eliminating the requirement for disassembly of equipment, eliminating time required for cleaning and steaming operations, thus increasing available capacity (in this case by 40%).
Although a full cost analysis was not carried out, it is clear that the cost savings are significant, notably in terms of the number of extra days of manufacturing that become available, along with significantly reduced WFI requirements.
Of course, disposable technology requires further testing and fine-tuning before being suitable for implementation on a routine basis. In particular, the issue of supply chain security—validating a second source—must be addressed. With regard to integrity testing of disposable systems, an industry consensus on what are acceptable and sensible detection limits would be helpful. This is where the industry association disposable user groups within the ISPE, PDA, BPSA, and ASME must work together to provide one unique recommendation.
Andrew Sinclair is the managing director and Miriam Monge is the vice president of marketing and disposables implementation, both at Biopharm Services, Chesham, Bucks, UK, +44 1494 793 243, firstname.lastname@example.org Miriam is also the European chair of ISPE's Community of Practice for Disposable Technologies.
The authors would like to thank Nigel Bell and Ernie Jenness for their time and active collaboration in preparing this column.
1. Sinclair A, Leveen L, Monge M, Lim J, Cox S. The environmental impact of disposable technologies. Supp BioPharm Int. 2008 Nov:4–15.
2. Cronin E. Disposables and containment technology in biomanufacturing: managing risk, reducing cost. ISPE Strasbourg Conference; 2009 September 28–29; Strasbourg, France.