21 August 2020
Facility and equipment design are important, but the team and its experience matter most.
Through its Operation Warp Speed program for COVID-19 vaccine manufacturing, the US government is paying manufacturers and contract service providers to scale up the manufacture of specific vaccine candidates. If those specific candidates are not successful in the clinic, those facilities must be able to quickly switch to production of different vaccine candidates that have been approved.
While this approach sounds like a practical approach to accelerating vaccine manufacturing, rapid changeover of biologic production process carries numerous challenges. There are a few different strategies for overcoming these challenges, with key components including facility design, equipment selection, operational considerations, and the use of appropriate plant management systems.
Challenges to rapid changeover come from many sources, including the equipment, room configuration, documentation, people, and environmental monitoring, according to Sebastien Ribault, head of end-to-end solutions at MilliporeSigma.
Several activities must be performed in a facility to avoid any risk of cross-contamination between Product A and Product B, in particular via a thorough cleaning-in-place of all equipment surfaces in contact with intermediates and the end product, Thibaud Stoll, global head of commercial biologics operations at Lonza, specifies.
For certain biologics, most notably viral vectors, vaccines based on live viruses, and spore-formers, precautions must be taken to prevent spread through the air and more extensive cleaning protocols are generally required, typically with airborne peroxide methodology, says Katarina Stenklo, enterprise solutions commercial activation leader with Cytiva. Any live biological agents, whether they be the host organisms or adventitious agents, must be effectively removed/inactivated from HVAC, facility, and equipment surfaces (both exterior and product paths) prior to introduction of a subsequent product, adds Syed T. Husain, senior vice president and CDMO business unit head at Emergent BioSolutions.
Stainless-steel equipment specifically presents a common challenge, as it requires cleaning and validation of product contact surfaces before the equipment can be used for a subsequent project, according to Evan Shave, director of biomanufacturing—global network operations for Thermo Fisher Scientific. Cleaning and sterilization of stainless-steel equipment is well understood, but often “overdone” in terms of cleaning and rinse times, mostly due to conservatism or a lack of time to properly optimize the process, adds John Machulski, vice president of engineering for Catalent Biologics.
Changeover of processes performed in a ballroom setting can be even more difficult than for processes run in individual suites due to the added risk of cross-contamination with other processes on top of concerns regarding product carryover, notes Steve Gravallese, enterprise solutions program director at Cytiva.
Stoll adds that some product-dedicated equipment must also be installed, in particular chromatography columns with packed resin for drug substance purification. “All these activities may potentially be quite long and on the critical path if not optimized and sequenced properly, and if the facility layout has not been designed accordingly,” Stoll states.
For drug product manufacturing, it is critical to have a lean process design due to its highly kinetic nature, according to Machulski. “Although barrier isolation technology provides the highest level of aseptic processing, long bio-decontamination cycle times remain one of the biggest challenges for achieving a rapid changeover,” he says. Stoll also notes that given the completely different types of equipment, changeover times are difficult to compare. “A change in vial format may require some significant setup activities for a filling line; the number of such changes can be optimized via the proper yearly planning and sequencing of campaigns,” he observes.
For contract manufacturers in particular, the biggest difficulty is the need for processing equipment flexible enough to accommodate different processes/scales corresponding to molecules from different clients. “This challenge is more likely to apply to drug substance rather than drug product because drug substance processes typically have significantly more variability between different products,” Shave notes.
Strategies for optimization of process changeovers differ because the equipment and room configurations for each process are different, but all are driven by the same constraints and rational, according to Ribault. “A combination of primary (process design), secondary (facility design and operation), and procedural controls and studies should be used,” states Husain.
Stoll identifies three key approaches to optimizing changeover activities: making them as short as possible, performing them during “hidden time” or in parallel, and reducing the number of changeovers by running longer campaigns. “Operational excellence/lean methodologies can be quite powerful for optimizing changeover processes, as can the use of redundant equipment or dedicating packing rooms for chromatography columns. In the latter case, there is additional capital expense, but it is usually a good investment,” he says. Running longer campaigns, though, carries a trade-off with the optimization of product inventory.
The ultimate goal, according to Gravallese, is optimizing the facility around unit operations so they can be segregated where open processing cannot be avoided and staggered changeovers are possible. “It really comes down to identifying the best methodologies and designs to stagger processes in facilities without impacting operations in the balance of the site,” he states.
Properly optimizing cleaning and sterilization cycles where stainless-steel equipment is used, validating procedures, having a well-trained staff, and having a robust yet simplified supply chain are keys to facilitating rapid changeovers, according to Machulski. “Additionally, ready-to-use primary and secondary components can be helpful, along with automation and robotic technology for drug product fill/finish manufacturing,” he says.
Ribault also asserts that it is important to look across the entire value chain and consider how to ensure the interface between process development and manufacturing works well; another consideration is to put together a team that will make the project a success in record time. “You do these things by having templates in place for process development and manufacturing that reduce the transition time. So, while rapid changeover is certainly an integral aspect of operations, it is important to keep in mind that it is one piece within the entire value chain,” he says.
In addition, a quality risk management approach may be applied to assess and continuously improve established changeover processes, according to Nestola. “All processes, including changeovers, can be improved with investment of money and resources, parallel activities, equipment design improvements, and standardization,” he asserts.
Facility design plays an important role in facilitating rapid changeovers. Inclusion of multiple upstream suites can enable better utilization of downstream operations because upstream processing takes much more time, according to Stenklo.
For a multi-product downstream suite, Shave notes that it can be better to have the plant broken up into two or three segregated smaller rooms versus a single ballroom so changeover can start as soon as the unit operation is finished. “This approach affords the opportunity to increase facility throughput,” he says. A phased approach allows for proper and thorough cleaning as the process completes, agrees Husain. In addition, all surfaces should be smooth to allow for easier yet effective cleaning/disinfection, he notes.
Separate mechanical air handling systems should be used for independent spaces to allow some rooms to be shut down while others continue to operate, adds Gravallese. Door interlocking alarm systems are equally important because they ensure that adjacent process spaces remain separated during changeover/cleaning. The ability to monitor spaces quickly is also essential so they can be released back to operations, he adds. “Environmental monitoring of different rooms is necessary to ensure they stay within qualified requirements (temperature, pressure, humidity, bioburden, etc.) Some sampling is manual, but where possible automation of sampling can help speed up changeovers,” Gravallese says.
Other important facility design aspects for rapid changeover, according to Machulski, include: quality by design, design for manufacturability principles (i.e., lean, single-minute exchange of dies [SMED], etc.), integration of lean operating principles such as 5S for optimal equipment, material and personnel flow in the manufacturing suite, and the establishment of SMED quick changeover principles to ensure efficient reconfigurations of the equipment.
Changeovers can also be facilitated if extra rooms are included in the facility where cleaning-in-place activities on equipment can be performed in parallel, Stoll observes. “It’s not just about one aspect, but all of the aspects, including the size of the corridors, equipment placement in the suites, management of sampling, and environmental monitoring working together,” asserts Ribault.
The so-called “facility of the future,” concludes Nestola, would allow rapid changeovers due to its modular approach and because it is fit by design to accommodate single use and minimize any possible cross-contamination while still allowing detection and prevention of possible deviations.
In general, the equipment developed for the biopharmaceutical industry includes built-in functionality—both hardware and software—to make changeovers easier, according to Stenklo. If the same equipment can be used for multiple different processes to avoid having to schedule time during the changeover to move equipment in and out of storage, then changeovers can be faster, adds Shave.
Closed-system design and operation in and between unit operations also mitigates the potential for cross contamination, states Husain. Closed processing is essential because it provides a better response when using a risk-based approach, adds Nestola.
Single-use equipment is therefore one of the biggest equipment-related solutions for facilitating more rapid changeovers. “Pre-gamma irradiated single-use flow paths for all unit operations, standardized pre-sterilized tubing assemblies to connect unit operations, and aseptic quick connectors (rather than welding or heat sealing) are all designed with features that enable rapid changeover,” Shave observes.
The key advantage of single-use equipment is the elimination of cleaning and cleaning validation steps, which significantly reduces cleaning time, according to Stenklo. “With optimized consumables and consumable assemblies, the equipment can be specifically designed for the process and the facility as well,” she adds.
Single-use equipment allows a changeover in a matter of hours because it involves closed bags, according to Ribault. Both the monitoring and documentation steps are simplified because there is lower risk and the process is less complex with single-use versus stainless steel equipment. “Many people who are trained on single-use equipment find it beneficial due to its simplicity and speed of changeover,” he says. Ribault does add, though, that if a hybrid approach is used, all aspects including equipment and sampling, need to be taken into account to ensure there are no bottlenecks that can slow down the changeover process.
Shave adds that flexible hardware with single-use product-contact flow paths are ideal. For instance, he notes that a tangential-flow filtration skid can be equipped with small and large pumps and the ability to take small and larger single-use tubing sizes to accommodate a wide range of processes.
Emergent’s Baltimore Bayview facility, which is the company’s pandemic response facility designated as a Center for Innovation in Advanced Development and Manufacturing (CIADM) by the US Department of Health and Human Services, uses flexible manufacturing and single-use bioreactors to respond to the COVID-19 pandemic. “Flexible design will help enable us to complete rapid changeover and meet the stringent timelines required for producing COVID-19 candidates,” observes Husain.
Even with conventional stainless-steel equipment, there are steps that can be taken to reduce changeover times. “The ability to isolate the process equipment and transfer piping for clean-in-place (CIP) and steam-in-place (SIP) operations is critical,” asserts Gravallese. “Staggering the CIP/SIP of equipment and transfer lines can also accelerate changeovers by ensuring that the critical equipment can be isolated for priority cleaning to facilitate the start of the next campaign. Once all critical equipment and piping has been released back to operations, all secondary equipment can be cleaned for changeover, without impacting the production schedule,” he notes.
Ready-to-use components used within a filling line also allow for the cleaning step in fill/finish operations to be completely removed, while an automated high-speed filling line provides higher capacities than a traditional filling line. “Both of these design elements theoretically allow for more production runs to occur,” Machulski observes. He adds that high operational availability is achieved by reduced line clearance times and changeover times. For example, by design there are 40% fewer parts to change on an automated high-speed filling line than a traditional vial line, and 20% fewer parts to change than a traditional syringe line. Automated servo motor adjustments and robotic arms are the enablers for this step change and result in a reduction of up to 30 minutes per changeover, according to Machulski.
Implementation of rapid real-time testing for bioburden and endotoxin and total organic carbon can also be an advantageous best practice if equipment cleaning is required during change over, according to Shave.
In addition to facility and equipment design, operational aspects can contribute to more rapid process changeovers. In particular,Stoll points out thatautomation and digital tools are enabling technologies for streamlining changeovers, such as via optimized scheduling of activities and electronic checks and instructions to minimize the risk of errors. “The right manufacturing execution system (MES) can help your facility of the future be both agile and compliant,” asserts Nestola.
Automation software can provide guidance in ensuring that a single-use flow-path is properly connected, thereby saving time performing manual validation, Shave adds. The software can also generate automated batch records of installation and validation, saving the operator time doing manual paperwork. Augmented reality tools, meanwhile, can speed up the changeover process by walking the operator performing the changeover through the process as it is completed.
When one automation platform is used to integrate various pieces of equipment and provide additional functionalities, the ability to scale the whole system with the technology is facilitated, according to Stenklo. “Release handling is much easier when batch reporting, the data historian, and data analytics are maintained in a central place,” she says. “Process data can be accessed while a process is running without the need to gown up and enter the suite. Similarly, systems have been developed to support more rapid changeover approaches.
In fact, instead of weeks of review, a facility of the future can achieve real-time release without quarantining the product, notes Nestola. “In addition,” he says, “use of analysis of the data collected by the manufacturing execution system can provide information about trends during different changeovers and their possible impacts on the product, if any.”
It is important, though, notes Husain, that automation be designed to allow for plug-and-play operation. “Generally, islands of automation concepts are used. A flexible data historian design also helps in allowing for equipment flexibility yet proper operational control and data analysis,” he explains.
For final drug product manufacturing, Machulski highlights the short bio-decontamination cycle times achieved through optimized injection of hydrogen peroxide vapor and use of catalytic aeration technology within automated filling lines, which enable filling of thousands of components within minutes to hours depending on the total production run. “This allows for more production runs to happen within a set timeframe. Additionally, these automated lines mitigate the risk of human contact with the product, allowing for less variability in the time taken for a human interaction and hence quicker filling times,” he observes.
It is important to keep in mind, though, that automation and software are just tools, not an objective, per se. “They don’t speed up changeover, but can slow it down. Since a facility is the sum of equipment, automation, and people, etc., it should not be considered separately,” Ribault asserts.
In fact, anticipation, training and processes including the mapping of activities and their management through solid project management procedures can eliminate most of challenges, according to Ribault. Electronic or paper procedures that guide shop floor people through all of the steps are key to ensuring fast and error-free changeovers, particularly when combined with MES, electronic batch record systems, and automation, agrees Stoll.
To facilitate rapid changeovers, an overall plant management system should have an adaptive scheduling system that automatically adjusts in response to changes, Shave adds. Supply chain management to ensure supply of consumables is also important, according to Stenklo.
Specific components of a good plant management system include electronic batch record capability, role-based recipe management that optimizes each stage of a recipe lifecycle, data integrity features to help prevent documentation or human errors, and data analytics to monitor, control, and predict any possible variation in the process, according to Nestola.
Overall, Ribault notes that the most important features in a plant management system are people and expertise. “The expertise to run a plant is not in the systems or equipment, but in the team and its experience, including quality, regulatory, and technical experience,” he asserts.
With COVID-19 and the focus on accelerated development and production of potential vaccines, the industry is entering “brave new territory”, according to Gravallese. “It will be even more critical under these circumstances to rely on past experiences to accelerate the approach,” he says.
Any accelerated strategy that involves pushing the boundaries of the usual regulations should be identified up front and discussed with the regulators as early as possible (e.g., use of stable clone cell bank or transient transfection for good manufacturing practice production), Shave stresses. Vaccine developers also need to ensure flexibility with respect to the expected required manufacturing capacity, according to Stoll. “One approach is to work with contract development and manufacturing organizations (CDMOs) to complement internal capacity,” he observes.
When selecting CDMO partners for accelerated COVID-19 projects, vaccine developers should first conduct a risk analysis to identify their capabilities and any gaps related to the projects, according to Gravallese. “It is rare to find a perfect match, but it is important to find CDMOs with the platforms, technologies, and capacities that require the minimum level of retrofits and downtime and will allow for a reasonable best approach. Where customers lack specific knowledge, CDMOs should be able to make assumptions based on their experience combined with good engineering practice, good quality practice, and the available tools in their toolboxes,” he concludes.
It is also important today for CDMOs to specialize in a couple of vaccine platform technologies, adds Nestola. “Most of the vaccines in development are based on one manufacturing platform and many viral vectors processes are similar to each other. The same goes for the mRNA platform, where processes are similar between different candidates. By using multiple platforms, the risk for failure can be mitigated,” he explains.
In addition, given the current increased lead time of most of the critical consumables, Shave says it is imperative that processes be developed using platform raw materials that can be purchased upfront before the process is finalized. “If a CDMO is involved, there will be a need for the drug developer and the CDMO to partner closely together to balance and adjust processes as needed during these unprecedented times,” he remarks.
CDMOs also need to agree with clients on a rapid approach to document review, according to Shave. As an example, he points to the use of templated documents, which can avoid or significantly minimize the need for client review of every batch record. In addition, quality systems may require some flexibility in the usual practices around document control to account for last-minute changes, Shave adds.
One challenge when entering new territory is the rapid pace at which a larger number of activities are occurring. Standardization can, according to Gravellese, help expedite the process. “While the initial reaction of many people is they don’t have time to fit standardized approaches to their specific processes in such an environment, the truth is that standardization actually provides more flexibility. Even if standardization is only achieved on a microlevel, the focus can then be directed to items that are critical and for which true solutions don’t yet exist,” he explains
To start, facilities with segregated production suites should be selected to enable processes to be up and running quickly, but at some point, optimization should be pursued to increase throughput on the same equipment, according to Stenklo. “Similarly, while standalone equipment might provide the fastest pathway to an engineering run, integration of equipment on a single platform will likely provide more efficiency in the long term,” she elaborates.
The parallel investment in CDMOs and vaccine innovation is unprecedented and critical to being able to rapidly respond to the COVID-19 pandemic, Husain concludes. “The potential success or failure of a vaccine candidate cannot be predicted. It’s important that CDMOs continue to focus on supporting all innovators and have clinical and commercial capabilities to continuously pave the way for innovation and development of life-saving medicines for patients,” he says.
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