Kjell Johansson, president, manufacturing services Europe, Recipharm: The industry is seeing an increasing degree of automation across manufacturing processes, as well as heightened awareness of the need for operator/product segregation. There is now greater recognition that human beings present the most significant risk to contamination in an aseptic environment. Consequently, there is growing focus on putting more innovative and stringent measures in place to minimize the potential for contamination.
Rapid microbiological methods are also growing in popularity due to their ability to reduce manufacturing time and enhance the performance of environmental monitoring. These methods can help reduce feedback time, enabling possible contamination situations to be quickly addressed.
Colin Mackay, chief executive officer, Symbiosis Pharmaceutical Services: The development of robust single-use manufacturing technology has been a step-change in the sector, enabling more efficient fill finish activity. Rapid access to manufacturing slots and quick turnaround times are critical factors for our customers when selecting a contract partner and single-use technology is one reason that we can offer this level of service. We have also witnessed a continued drive towards outsourcing due to the specialized nature of some of the manufacturing challenges that companies are facing.
Christian Dunne, global product manager, aseptic, ChargePoint Technology: One of the latest challenges in aseptic manufacturing is the increasing need to process sterile potent compounds such as sterile active pharmaceutical ingredient (API) powder and oncology drugs, which require all the parameters for aseptic manufacturing while containing the process from an operator exposure perspective. These two methods of manufacturing are sometimes at odds with each other in terms of general philosophy; aseptic manufacture equals positive pressure and contained manufacture equals negative pressure. Combining the two is now a common challenge for both manufacturers and equipment suppliers alike.
CP: Are you seeing a shift in customer demands and expectations?
Johansson: Yes, aseptic manufacturing is subject to increasing scrutiny and, accordingly, the needs of our customers are evolving as they work to align themselves with the various requirements from the global regulatory bodies. We are seeing growth in customers approaching us with compliance challenges and are working with them to both meet and exceed new guideline requirements. For example, extractables and leachables (E&L) testing continues to be a focus area, allowing us to identify and test all possible impurities in contact with a drug. Many customers are demanding testing and analysis beyond the regulatory requirements to achieve a deeper understanding of the risks associated with any potential contaminants. A number of analytical techniques are growing in popularity, including HS-SPME-GC-MS, GC-MS, UPLC-UV-HRMS/MS and ICP-MS.
Mackay: More than ever, customers are under increasing pressure to demonstrate the success of their molecules at an early stage. This is particularly the case for small biotechnology companies that need to demonstrate progress and value accretion to investors. As a result, there is a demand for shorter lead times to access aseptic manufacturing slots and the subsequent release of the manufactured product so that it can be used for its intended purpose. In order to allow this, we are seeing a greater requirement for flexible and multi-product sterile manufacturing capabilities.
Dunne: Yes, the need for greater system validation and more real time monitoring which may help to spot issues early rather than wait for intermittent sterile sampling later in the process. This need for greater validation has certainly manifested in the sporicidal spray and wipe philosophy, which is now being replaced in many cases by validatable bio decontamination systems. Room isolators, restricted access barrier systems (RABS) and transfer devices are now all employing this more stringent approach in aseptic manufacture.
CP: Are facilities for aseptic manufacturing changing?
Johansson: Yes, today’s facilities have been designed to ensure a high degree of segregation between process steps and to limit product exposure to the environment. To support this change, high levels of automation are being adopted to minimize operator intervention and, therefore, the risk of contamination. Additionally, regulatory requirements, such as EU GMP annex 1 on vial capping, are having a considerable impact on how we approach processes within manufacturing facilities.
Mackay: In today’s environment, flexibility is key. Modern facilities need to be more multi-product use oriented and flexible to meet individual project requirements, which reflects the evolving drug pipeline. Our facility in Stirling, Scotland, has been purpose-built to reduce development time while maintaining absolute GMP compliance. The role of automation is also becoming increasingly essential in aseptic manufacturing to increase output and sustain process efficiencies.
In any cleanroom environment, there are two potential sources of contamination: the incoming air, which must be carefully controlled, and human beings, which are naturally a rich source of bacteria. To prevent contamination from the latter, there is an ongoing debate among quality and manufacturing experts regarding the use of RABS and isolators in aseptic manufacturing environments. In our experience, the use of RABS in place of more cumbersome fixed wall sanitized isolators can deliver significant time savings to certain sectors of the industry, speeding up the manufacturing process and providing the flexibility to deliver product in a time-efficient and responsive manner.
Dunne: Open handling of sterile product in grade A rooms is now being replaced more often by sealed transfers and barrier protection. The benefit in using these technologies has been gaining momentum for the last 10 years and is now actively encouraged by guidance documents and regulators as the safest approach in achieving a greater level of microbiological assurance. Techniques for sterile powder handling which historically were used in potent compound manufacture are now being adopted in sterile manufacture particularly in the charging of solution preparation vessels, where sterile powder transfer valves are now being employed instead of high level room grades, isolators or RAB systems. We are also seeing a more considered approach to area classification on filling lines combining both RABS and isolator sections on the line instead of classifying the whole line as needing an isolator.
CP: What are the greatest challenges faced by aseptic manufacturers?
Johansson: Finding the optimum balance between cost and quality. Manufacturers face a conflict every day. On one hand, they are dealing with increased pressures to maintain manufacturing facilities to ‘cutting-edge’ standards and to employ the most skilled workforce. But they are also faced with the need to reduce the costs of final products. Evidence of this can be most clearly seen in the development of generic products, which are currently the primary targets of government cost reduction strategies.
Mackay: Perhaps the greatest challenge faced by aseptic manufacturers is the high regulatory scrutiny of the industry, which is understandable given the nature of the processes. Of course, the need to offer rapid access to slots and to meet tight timescales to get product to clinical trials is a daily challenge and those contract manufacturing organizations (CMOs) that can offer this flexibility are well positioned for growth. Similarly, the trend towards smaller batches for smaller patient populations is driving down the number of vials that may be required for a particular product, meaning facilities need to be able to adapt to quick turnaround times and be nimble in managing new product introductions.
Dunne: There are several challenges faced by aseptic manufacturers. Firstly, legislation and guidance documents are catching up with proven solutions within the industry and minimizing risk while maintaining cost. Secondly, increasing the assurance level across a process will always increase the cost. Finding the balance between an effective system for drug production and one that is safe and cost effective is an ongoing challenge.
CP: Do you believe the current regulations for aseptic manufacturing are fit-for-purpose? That is, are they helping to promote quality and innovation while minimizing risk?
Johansson: Although considerable effort has been made in establishing guidelines that promote innovation, such as ICH Q8, Q9 and Q10, they can sometimes have a counter-effect, particularly when they are too prescriptive. Regulators need to account for the fact that in today’s market, technology advancements, new materials, software and equipment are being made available much more frequently, making current practices quickly obsolete. Consequently, it is critical that new guidelines focus on the target to be achieved more than the processes necessary to achieve it.
Mackay: The CMO must ensure that the processes employed and materials to be used are fit for purpose ultimately this is a necessity for patient safety. This can be achieved by sourcing materials from manufacturing and supply chain sources which are operating to EU GMP. The increased expectation placed on the releasing QP to ensure GMP assurance in the clinical supply chain has certainly been a step towards minimising risk while promoting quality, however this demands a level of experience to facilitate the QP and the CMO to be able to manage that challenge without negatively impacting either innovation or the over-arching timeline.
Dunne: In many ways, yes, the regulations do fit many applications although as new products and processes develop the regulations need to change to keep up with industry requirements. Unfortunately, international standards are not updated as quickly as industry demands although it is understood that major changes to standards cannot be taken lightly and need time to be reviewed and considered before implementation.
CP: What are the latest developments in sterility testing and environmental monitoring?
Johansson: Rapid microbiological methods are evolving and replacing traditional techniques, even though there are still misconceptions that they will not be accepted by regulatory bodies. Several qualitative, quantitative and identification tests are already available, with more expected in the near future. Obviously, the implementation of these types of methods in contract manufacturing must be through agreement with customers.
Mackay: Multi product manufacturing sites means that cross contamination control, product testing and appropriate environmental monitoring will be increasingly important.
CP: How do you see the future of aseptic manufacturing?
Johansson: The demand for aseptic manufacturing will remain high. In the development of new biotech products, many manufacturers simply cannot afford the costs to have their manufacturing facilities sterilized to this degree. Outsourcing presents the most cost-effective and time-efficient option.
We are going to see new technologies helping to further enhance sterilisation assurance levels, improving processes and reducing associated costs. We will also see approaches evolving to help manufacturers deal with new requirements associated with personalized medicine.
Mackay: The drive towards personalized medicines will mean that aseptic manufacturing facilities will need to be able to adapt to different batch quantities and multiple products. This is a major shift from traditional contract facilities, which traditionally would focus on a single, or only a few, products.
As we move forward, the industry is going to comprise fewer small CMOs which can deliver the specialist skills and operational flexibility needed to help biotech and pharma companies move through the stages of the clinical development process in a speedy, nimble and agile manner while ensuring regulatory compliance of the highest order.
Dunne: I see the demand for aseptic manufacturing increasing year on year. The increased need for injectable drugs together with sterile APIs appears to be fuelling much of its growth. The demand for more sealed transfers and barrier containment to improve sterility assurance will continue to grow and many of the old processing techniques will evolve to become more robust. An even greater level of process feedback and monitoring is inevitable to ensure the final drug product is as safe as possible.