The fill/finish process of aseptically prepared drug products requires sophisticated technology and machinery in a highly controlled GMP environment (see Figure 1). Single-use fill/finish assemblies must meet stringent requirements to ensure flow-path sterility and integrity, ensure operational safety, and provide fill-volume accuracy accordingly.
Traditional fill/finish systems are made up of complex components that require assembly, cleaning, and sterilization prior to aseptic filling. These operational steps often include handling of open aseptic connections, such as tri-clamp, thus, presenting small parts of the flow path to the surrounding environment and allowing the possibility of contamination and sterility breach. Time pressure and rotary piston-pump systems, which are still predominant methods for dosing/filling, often require aseptic component assembly. The associated risks of cross-contamination, particle, or microbial contamination are minimized by using validated clean-in-place (CIP) and steam-in-place (SIP) procedures to ensure high probability of sterile final product flow paths.
Traditional stainless-steel fill/finish facilities are considered inflexible, with long change-over times and high operating costs. Cleaning, decontamination, assembly, CIP, and SIP during product change-over create a bottleneck in the filling line operation. Validation of cleaning and sterilization processes and effort for cleaning validation analytics are lengthy, labor-intensive tasks to ensure repeatability of the process. These steps contribute to creating a bottleneck when time to market is essential.
The nature of these fixed systems is at odds with a market that is undergoing rapid transformation. Smaller batch sizes, more varied product portfolios, and intensifying pressure to speed time to market and reduce costs are not compatible with traditional fill/finish systems or their capacity usage profile.
A number of pharmaceutical manufacturing steps are increasingly moving toward single-use solutions to enhance operational flexibility, reduce contamination risk, and reduce capital investment in facilities and equipment. Elimination of cleaning at various stages in the manufacturing process brings a higher level of safety to the operator. While the expected benefits of single-use technology are well recognized, actual examples of what single-use technology can deliver within fill/finish operations are now being realized.
Roche Diagnostics GmbH (Mannheim, Germany) recently implemented a single-use assembly (pre-assembled, gamma-irradiated, ready-to-use, tank-to-needle concept) in a state-of-the-art multi-product final filling suite with isolator technology (see Figure 1). This article describes a novel approach to sterile drug product manufacturing and the benefits delivered in terms of efficiency and flexibility. The authors provide an overview of the qualification and validation approach, designed to effectively mitigate potential risks and ensure regulatory approval.
Roche Diagnostics sought to implement single-use technology in fill/finish using isolator filling technology with the following key objectives in mind:
- Reduce risk of cross contamination
- Reduce risk of microbial contamination by limiting the number of valves and manifolds traditionally used for transport of media and buffersOptimize the capacity of the filling line and improve efficiency by shortening time required for setup and changeovers as well as minimize product loss
- Reduce complexity, installations and interventions within filling isolator, such as no CIP/SIP equipment installation; reduced capital investment; elimination of cleaning and sterilization costs; elimination of SIP/CIP maintenance costs and substantial energy costs for SIP; placement of peristaltic pump rack outside the isolators’ aseptic core in Grade D environment for ease of set-up and maintenance
- Increase flexibility for multi-product filling by ensuring applicability for high throughput plant (three shifts per day, five days per week) and small-scale products and/or clinical demands.
A major factor that helped drive this project was Roche’s corporate culture embodied by the company’s mission, “We Innovate Healthcare,” which guides not only drug discovery and development but also the adoption of novel technologies for manufacturing. At the time this project was initiated, no specific regulatory guidance existed regarding the implementation of single-use materials at the final filling stage, which is the most crucial unit operation in contact with the liquid-drug product before it reaches the patient. Lacking a true precedent, a crucial requirement for commercial implementation was the establishment of a risk-based strategy and a rationale to qualify and validate this application of single-use technology at the Roche Mannheim site.
In addition to the need to create a robust qualification and validation strategy, a number of technical challenges were present. The filling facility was designed to take full advantage of a closed-system sterile flow-path, achievable with single-use systems that are designed with sterile-to-sterile connectors. Syringe filling with a tray filler technology (INOVA HS 6, high-speed line, 10-needle stations) occurs in a Grade A isolator that is contained within a Grade D environment. The design leaves portions of the final transfer assembly that are holding sterile filtered drug product in a Grade D environment (see Figures 2 and 3) including the final sterile filtration step and peristaltic pump rack.
Because no single-use supplier had an off-the-shelf solution, a custom-engineered solution was required. In addition to standard library components, new components were designed to meet user requirements, for example, filling needles and a manifold for 10 tubings connected to 10 filling needles.
Beside the aspect to link storage tanks with the filling isolator directly, a single-use assembly is also used in a Grade C compounding area to transfer and filter the formulated bulk solution from the stainless-steel compounding tanks to the storage tanks, placed in the Grade D nearby. As conventional stainless-steel tanks are used with single-use assemblies in between, the system is considered a hybrid solution.
EMD Millipore was selected as the single-use assembly supplier and project partner of Roche in the development of this solution. Integrating single-use technology to work harmoniously with Roche’s specified hardware equipment required the addition of several single-use components that EMD Millipore had not previously qualified under the Mobius qualification program. As a result, components were being qualified in parallel with the single-use system design efforts. These components included the filling needles and needle cartridge and a 10-tube filling manifold that was the mechanism that delivered the sterile drug product from the reservoir bag into the 10 needles at the filling station. This approach added complexity to the project by creating more interdependency across discrete actions including co-development with sub-suppliers. Another implication of this approach was the need for a more system-specific qualification approach to meet project timelines and regulatory requirements.
Qualification and validation
To qualify and validate the use of single-use systems in Roche’s fill/finish process, a team with representatives from both organizations was chartered. This team reviewed the project needs, particularly how single-use technology was to be efficiently and safely employed, and established the underlying qualification principles of the individual components and the system itself. The team evaluated the interactions of the single-use assemblies with the manufacturing process, the manufacturing environment, and with the drug compound to ensure patient safety, and developed a qualification package to effectively mitigate and remove risk from the process. A key factor for success was a team approach incorporating members from Roche and EMD Millipore. The Roche team included a cross-section of expertise with representatives from manufacturing as well as quality, engineering, and microbiology groups.
The risk-based approach identified several key validation activities that were required to reduce the risk of a non-integral single-use assembly having an adverse effect on the drug product including:
- An integrity test that correlated to microbial ingress
- Validation of packaging
- Assemblies shelf-life validation
- Sterilization validation
- Extractable studies
- Product-specific leachable studies.
With portions of the single-use assembly containing sterile product in a Class D room environment, integrity of the system is crucial. Microbiological challenge testing identified 30 μm as the defect size that would allow ingress of bacteria under process conditions. To reduce risk, a special high-sensitivity integrity test (pressure decay) was developed to assure that defective units would be rejected (see Figure 4). Qualification of the high-sensitivity pressure-decay test identified the following as key parameters of the integrity test:
- Stabilization time was needed due to the initial stretching of the bag and tubing. Longer test time improved resolution of the test; however, process time is also important.
- Test pressure (100 mbar/1.5 psig) was selected as a compromise between better resolution of the test and negative effect of high pressure on the bag and assembly.
- Test temperature (i.e., room temperature) was constant within the duration of the test; enclosure helped maintain constant temperature, and a chart recorder measured temperature during testing.
- The resulting high-sensitivity integrity testing demonstrated statistically significant separation between defective and integral assemblies (see Figure 5).
The assemblies contained a number of new components that were not previously qualified by EMD Millipore. Additionally, the criticality of where the assemblies would be used warranted the conduct of an assembly-specific packaging
validation to complement the family approach that is used to validate EMD Millipore’s Mobius Assembly packaging (see Figure 6).
Packages of single-use systems that were exposed to worst-case simulated shipping conditions according to ISTA 2A (a series of drop, compression, and vibration exposure) were then verified for acceptable sterile barrier packaging integrity by bubble-emission testing and single-use system integrity by two integrity-test methods: a standard pressure-decay test of the complete assembly and the high-sensitivity integrity test of the critical flow-path downstream of the sterilizing filter. Packaging specifications and instructions with detailed photos are included on the single-use system drawings because properly designed and qualified packaging systems are crucial to the integrity of single-use systems.
The assemblies contained a number of new components specified by the client, which had not been previously qualified for post-gamma shelf life (see Figure 7). Assemblies were age accelerated in accordance with the Arrhenius equation where an elevated temperature is used to accelerate aging. Two sets of three single-use systems were aged on an accelerated basis for real time equivalence of 12 and 25 months. The aged systems were then tested by the high-sensitivity integrity test at the assembly shelf life and used for fill process performance to ensure filling volume accuracy at the assembly shelf life. The system approach to shelf-life validation was chosen to verify proper fit, form, and function of components in an installed and system state, providing a high degree of assurance that the system will function as specified over the full shelf life claim of two years.
Without quarterly dose audit history on new components, it was required to conduct a gamma-sterilization validation of the complete single-use system according to ISO 11137 to assure sterility at the 25k Gy minimum gamma irradiation dose (see Figure 8). Taking the single-use system specific approach to sterilization validation helped to reduce the risk of incorporating new components and materials that did not have a well-established sterilization history under the existing quarterly dose audit program. Ongoing sterility assurance is achieved by incorporating the new materials into the representative product that is used in the conduct of the quarterly dose audit program per the guidance of ISO 11137 (1).
Outcome of the validation approach
The validation activities were completed successfully and demonstrated the robustness of the single-use system design. Roche received positive outcome of an authority GMP inspection of their new facility, which focused on the use of single-use systems. The success of this project was attributed to the strong collaborative effort between Roche and EMD Millipore. The skill sets of both parties were important to developing a successful risk-based validation strategy.
As Roche and EMD Millipore partnered to implement this single-use fill/finish solution, a number of best practices were identified.
Roche brought together the various functional groups that would potentially benefit from this new process, including representatives from the user group, quality, microbiology, and engineering, while EMD Millipore also assembled a cross-functional team with product development, R&D, manufacturing, validation, and applications expertise. Early involvement of the affected teams was important.
The blended teams brought together the knowledge necessary to drive a successful solution. For Roche, it was their knowledge of the process and facility design, and expectations of local regulatory authorities on GMP design and validation needs. EMD Millipore brought expertise on single-use materials of construction, manufacturing expertise, and single-use systems and validation expertise.
A close, collaborative working relationship between the drug manufacturer and single-use supplier based on openness and transparency was important. Face-to-face meetings were encouraged and were a key element in helping to create a common understanding and set of goals between the two companies. Weekly teleconferences assured continuous alignment and project control.
Dedicated project management
With an undertaking of this magnitude, it was essential to put in place a dedicated project manager. As earlier stated, the project timeline required the qualification of component materials and integrity-test methods in parallel to the single-use system design, development, and qualification efforts, and the building and qualification of the filling equipment, which resulted in many interdependencies. Close monitoring of project action items and updating of timelines for deliverables was, therefore, required.
Stringent supplier management
Regulatory authorities have strongly recommended a thorough approach to supplier and sub-supplier qualification with a strong focus on the agreements and specifications in place with each, as crucial process steps, such as sterilization, are no longer under direct control while outsourced. Also crucial to success was Roche having access to EMD Millipore sub-suppliers. This process was facilitated by the strong relationships EMD Millipore had in place with their suppliers, which allowed Roche to readily access audits across the entire value chain including EMD Millipore’s sterilization provider and microbiological contract labs.
Frequent day-long “Man at the Plant” visits to the EMD Millipore facility, which included project team members from Roche, allowed both partners to build trust and share expectations around required processes in assembling, testing, and overall handling of the single-use systems. EMD Millipore was able to adapt to evolving requirements surrounding the final fill/finish processes in aseptic/sterile manufacturing of drug products.
Engagement of regulatory authorities
Faced by new technologies that lacked guidance from official GMP documents so far, Roche decided to present their facility design, new technology concepts, and control and qualification strategies to local authority bodies as well as to FDA in an early stage of the project. Feedback was included in the further qualification and validation program.
The single greatest challenge of this project was the need for both teams to step into “grey space” to deliver on the project requirements. On one hand, this was a key challenge to overcome. On the other, it was a key factor in how the team was able to function in a highly collaborative way. Neither company, nor any individual team member, came into the project with a deeply rooted methodology or process for achieving a successful outcome. The team truly had to develop the solution to the challenges together. Discussion and debate over the best path was often intense as the stakes were high but the dynamic always remained collaborative. Team members also remained highly committed throughout the project, motivated not only by professional goals and objectives, but a personal commitment to advancing and improving a crucial pharmaceutical manufacturing step. Experience, however, yields efficiency and many of the technical hurdles that were difficult to overcome in this project are now much less challenging for future projects. With a greater knowledge of regulatory expectations, a sound risk-based qualification approach, improved component library, and greater understanding of high-sensitivity integrity testing, both EMD Millipore and Roche are better positioned for future projects of similar scope.
1. ISO 11137, accessed Aug. 19, 2013.
The authors wish to acknowledge the following members of the Roche Disposable Project Team for their continuous support, passion, and contribution: Frank Jäger (Site Engineering), Dr. Tobias Vocke (QC Microbiology), and Udo Klotz (Quality Assurance).
About the Authors
Dr. Andrea Detroy* is head of QC packaging materials projects, Medical Devices & Disposables, Roche Diagnostics GmbH, Mannheim, Germany; Dr. Christian Matz is global project manager, Biologics Manufacturing Science and Technology, F. Hoffmann-La Roche Ltd, Basel, Switzerland; Mark Leykin is senior validation engineer, EMD Millipore;Ernest Jenness is Mobius product manager, EMD Millipore; and Ross W. Acucena* is regulatory consultant, Provantage Services, EMD Millipore.
*To whom all correspondance should be addressed, [email protected] and [email protected]
This article appears in the BioPharm International 2014 Single-use Systems eBook.