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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
Equipment and facility cleaning is crucial, with more extensive protocols needed for some biologics.
Rapid changeover of biologic production processes carries numerous challenges. 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.
The traditional method of completely stripping down all equipment and installing dedicated materials and components for each product has proven to be a cumbersome and costly process for multiproduct facilities, adds Piergiuseppe Nestola, senior platform technology consultant at Sartorius. “It is not unusual for changeover to require weeks to complete when traditional methods are followed. With the changing industry tide favoring multiproduct manufacturing facilities, methods to enhance efficiency without sacrificing quality or safety are needed,” he says.
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.
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.
Cynthia Challener is a contributing editor to Pharmaceutical Technology.