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A holistic approach to validation and quality assurance is essential.
Biologic drugs are highly valuable in treating diseases, and assurance of sterility and proper final product quality is essential. Appropriate testing must be conducted to ensure the filled vials, syringes, cartridges, etc. contain the correct quantity of sterile, contaminant-free product. Aseptic process simulations are crucial for the assessment of aseptic filling capabilities.
The main goal during aseptic processing is to prevent contamination of the final product by microbes, particulates, or pyrogens. That prevention requires control of incoming materials and active supplier quality management, appropriate facility design, and advanced technologies involved in final formulation and filling processes, as well as consideration of sensitive product characteristics for biological drugs (i.e., sensitivity to light, temperature, mechanical stress, and oxygen), according to Oliver Kurz, vice president quality assurance at Vetter. Management of the ‘human’ factor also must be addressed. “A holistic approach considering all relevant aspects is key to the successful validation of aseptic filling operations. The intent is to validate the process from an aseptic perspective and any negative impact on sterility must be ruled out,” he asserts.
A number of elements must be incorporated to ensure quality filling processes. April Peters, director of quality assurance at Catalent, lists a full cleaning and sanitization program, area clearances to ensure reduced risk of product mix-ups, use of checklists for setting up equipment, and use of engineering tools to ensure that equipment is aligned and ready for operation among the essentials. She also notes that the use of an automated environmental monitoring system reduces operator intervention and risk of bioburden introduction, while automated clean-in-place and steam-in-place systems maintain sterility assurance for lines.
As importantly, Peters says, strong aseptic technique training and intervention programs provide a solid foundation to ensure operators maintain the Grade A environment. Frameworks must also be built to ensure smooth communication and proper escalation. “Catalent Biologics’ facility in Bloomington, IN, has incorporated a shop floor [quality assurance] QA team to observe operations and review documentation while fills are in progress. By partnering with manufacturing, corrections are addressed in a timely manner, reducing deviations,” she observes.
An assessment of each process step should be made to identify risks and describe the problems so that they can be evaluated and eliminated, or suitable management mechanisms can be constructed, according to Jim Donovan, vice-president of Pfizer CentreOne Operations. “A robust contamination control strategy (CCS) based on the risks identified ensures the required controls, preventions, and detection systems are in place to maintain product quality,” he states.
CCS, Donovan adds, is a holistic approach that considers but is not limited to aspects related to the environment (cleaning, sanitization, and environmental monitoring programs), the product/process (introduction of appropriate and effective bioburden-reducing and sterilization steps), the equipment and technology (fit-for-purpose, validated, and established through use of quality by design [QbD] and innovation), and personnel (trained and qualified).
The best approach, agrees Maria Lacourt, director of manufacturing operations for Alcami, is to conduct a holistic assessment of all the controls for the process and work toward a facility design that ensures proper execution of the process. “Beyond meeting requirements for the relevant room classification, the right equipment must be identified that enables optimum performance within appropriate containment systems such as isolators, which ensure reduced intervention of operators during aseptic processing,” she says.
In addition to proper training and qualification of staff executing the filling process, Lacourt also stresses the importance of managing the materials used in the process. “It is important to identify vendors, establish container closure integrity, and assess all of the properties of the materials that can impact product quality attributes,” she explains.
Sterile products can be aseptically filled into a variety of containers, such as vials, prefilled syringes, cartridges, and ampoules. While the general process steps (washing, sterilization/depyrogenation, filling) do not vary depending on the type of container processed, the complexity and details can vary significantly, according to Kurz. “With containers of different shapes and opening sizes, the aseptic exposure risk will be accordingly different,” adds Yiwei Li, senior engineer of drug product 4 (DP4) at WuXi Biologics.
The type of filling line—open Grade A, restricted access barrier system (RABS) or isolator—can also impact the number of steps involved, as can the method used for sterilization (filtration vs. thermal or chemical treatment) and whether or not lyophilization is required, according to Donovan.
Peters gives several examples. “Sterility assurance steps may vary depending on the components and filling line utilized for a product. Vials intended for one line may be ready-to-use and ready-to-sterilize for another filling line requiring washing and depyrogenation. Likewise, stoppers may be ready-to-use or need to be steam-sterilized and require additional processing steps.”
“Facilities that manufacture different product presentations or products filled in multiple container types may apply a family or matrix approach to qualification, although there should be a strong scientific and/or risk-based justification for doing so,” Donovan notes.
Aseptic process simulations (APS), also referred to as media fill studies, are critical to qualification of an aseptic facility, according to Li. They demonstrate, adds Lacourt, the ability of the filling process to operate consistently all of the time due to the design of the process, facility, equipment, and the training of the personnel. “The goal is to determine the microbiological risk associated with the performance of specific interventions and to challenge the way those interventions are executed in a simulation to confirm that they do not in any case affect the sterility of any manufactured product,” she says.
The APS is used to challenge the aseptic capability of the manufacturing process from the point of view of product, equipment, and component sterilization through container closure and subsequent processes that may impact unit integrity, adds Donovan. “Their purpose is to assess the entire process from beginning to end for weaknesses, which may result in microbial contamination of your final product,” he says.
In Vetter’s experience, according to Kurz, all aseptic operations should be assessed within a properly designed media fill. The testing should take into consideration careful inherent and corrective interventions as well as worst-case conditions like maximum permitted holding or duration times. “A comprehensive understanding of the process and its related aseptic criticalities that takes into consideration the variances during routine operations is essential to effectively conduct successful aseptic process simulations,” he remarks.
If done correctly, media fill studies provide information on processing operations that may affect the sterility of the final product and the performance of aseptic filling personnel under operating conditions, according to Donovan.
Media fill execution is also used to certify the personnel who will participate in the sterile manufacturing process, according to Lacourt.
Each APS must reflect the processes used on the targeted filling line and consider the specific processing elements used for manufacture on that filling line, states Donovan. “There are many elements to the manufacturing process that can impact or contribute to the sterility of an aseptically manufactured product. Balancing these considerations into the APS in a representative way will likely be a primary topic during a regulatory inspection. If the tests are performed correctly then the boundaries of the manufacturing process will be demonstrably represented by the media fill process. The negative growth of all units in the media demonstrates the line’s capability to aseptically manufacture,” he continues.
Critical components to consider for aseptic simulations include the frequency of media fills, the type of filtration used, the number of aseptic connections, the interventions, personnel qualification, environmental monitoring, allowable rejects, incubation temperatures and durations, who is completing the inspection, when samples are taken for growth promotion, accountability for filled units, and processing hold times, according to Amanda Adams, director of validation and quality engineering for Catalent. Others, according to Donovan, include the line speed, vial size, the number of operators, the length of time an operator can remain in the aseptic area, and equipment and component hold times.
Design of an APS should be scientific, risk-based, and mimic the production process, incorporating the contamination risk factors that occur on a production line, Donovan asserts. It should also be designed not to impede the recovery and growth potential of the media used in the process. In addition, the APS should reflect the overall process validation and simulate manufacturing operations including “worst case” activities and conditions as identified during risk assessment, according to Li.
“Setting up an APS program should include defining the aseptic processes, performing a risk assessment for each process, and evaluating each process for key control points and key factors that could present a risk of microbial contamination of the
product,” Li says, noting that at WuXi Biologics, a bracketing approach is used because multiple products or dosage forms are being filled or processed in the same facility.
Lacourt agrees that the key to performing successful media fill studies is development of a validation master plan that includes the strategy that will be followed, the components that will be used, the aseptic process times to be challenged, and the validation approach. Personnel must also be trained to ensure proper execution of each step and appropriate documentation must be maintained, she adds.
There is significant complexity involved in coordinating and scheduling an APS in a dynamic manufacturing environment that manufactures multiple products with variants in batch size, on multiple filling lines using variants in primary packaging components and supported by personnel on multiple shift patterns, according to Donovan.
In addition, often not everyone understands the need and requirements of media fills, Adams observes. It is also important to ensure operators understand that units that may be rejected during a routine manufacturing batch would not be considered a reject during a media fill. “Communicating the rationale to execute specific requirements can become a challenge as a result,” she comments.
The best way to manage these challenges, observes Lacourt, is the use of a structured program within a good quality system combined with planning the execution of media fills.
Demonstrating the quality of a filling process requires performance of effective and validated analytical methods. While each product will dictate what analyses are required, there are a few critical aspects that must be incorporated for those that are manufactured in aseptic filling lines, according to Adams.
If aseptic filtration is performed, then filter integrity testing data are key to support sterility of the batch. “Pre- and post-use filter integrity testing is essential to ensure that material is sterile-filtered. Implementing a filter testing protocol specifically for a given filter design can be challenging, but these difficulties can be overcome by working with filter or sterile filtration assembly manufacturers,” Adams says.
Periodic assessment of fill weights should also be conducted during aseptic filling to ensure that the required volume per container meets specifications, according to Adams. This information provides continuous feedback that the line is functioning as intended.
During media fills (APS), microbiological testing should encompass all of the testing completed during the manufacturing process itself, according to Lacourt, including pre- and post-use filter testing and sterility testing. Sterility tests, adds Adams, are critical to assessing the successful execution of aseptic processing, and procedures on sample collection and testing performance should be documented.
Each unit in a media fill must be inspected for turbidity by qualified inspectors to confirm that the aseptic filling operation can produce sterile units, Adams continues. Furthermore, the number of units filled and incubated should be documented, as should the number of units rejected pre-incubation with the cause for rejection, according to Li. After incubation, he notes that the number of units experiencing positive growth and their relevant tray identities should be recorded, and a detailed investigation conducted to determine the root cause and appropriate corrective/preventive actions.
Growth promotion testing of filled units is also important to demonstrate that microbes of concern can in fact grow under the processing conditions, adds Kurz. “Contact of the nutrient solution with all interior surfaces in the aseptically filled units must be assured. All filled containers should be incubated at two different temperatures with each followed by a visual inspection. Additionally, training of visual inspection operators including the methodology applied to identify microbiological contamination is important to consider,” he says. The resulting microbiological analyses and visual inspection will demonstrate the process capability for product sterility.
Environmental personnel monitoring during the execution of an APS is also important, according to Donovan, including viable and non-viable air sampling, surface sampling (contact plate and swabbing), and evaluation of process air and water for injection. The results are used to assess contamination controls in the manufacturing area and may be used in the event of a failure of the APS to help identify a root cause.
To ensure an effective simulation and result, Li observes that quality unit oversight of the entire process, including observation in real time, is required. “Ensuring appropriate quality oversight during media fills and performance of interventions is essential,” agrees Adams. “Quality oversight provides verification that media fills and interventions are performed and documented appropriately, ensuring the operations' validity,” she asserts.
“Specifically, observation of an APS performed by qualified personnel whose responsibility it is to document aseptic behaviors and maintain a log of any issues that may have occurred is important,” Donovan says. This information can be used as feedback on personnel behaviors for continuous improvement and for root cause analysis.
A final report providing an evaluation of the entire media fill and including a conclusion on the acceptability of the APS is also required, Li remarks.
It is not sufficient to run a media fill once. Routine requalification is an important part of the manufacturing landscape and is performed at a minimum twice per year per filling line, according to Donovan. “Performing ad-hoc APS beyond the routine requirement should be considered in response to significant modifications to equipment or facilities, changes in personnel, facility shutdowns, or as a result of a product sterility failure during routine manufacture,” he adds.
In addition, it is important to recognize that validation of the aseptic capability of filling operations is only one stage in the validation of the overall process, says Donovan. “Other stages that contribute to the success of the aseptic filling validation include: primary packaging container qualification, extractable and leachable studies, equipment qualification, filter validation, environmental monitoring performance qualification, personnel training and qualification, robust manufacturing procedure and batch record development, utility qualification, cleaning validation, cleanroom validation, and sterilization cycle validation,” he explains. Collectively these activities contribute to demonstrating the capability of a process to consistently produce product that will meet the pre-determined product quality attributes.
Aseptic filling involves complex interactions and therefore requires close coordination between the personnel, sterilized product, filling system/line, cleanroom, support facilities, and sterilized filling components to ensure the quality of filling operations for biopharmaceuticals. In recent years, aseptic filling technology has evolved from restricted access barrier systems (RABS) to isolator to even robotic aseptic solutions, drastically improving how drugs are produced in an aseptic manner, according to Li.
WuXi Biologics has several traditional fill lines, but recently added an aseptic filling facility leveraging Vanrx SA25 robotic aseptic filling technology (Vanrx), which greatly simplifies the aseptic fill/finish process via the use of a gloveless robotic isolator and ready-to-use (RTU) and single-use materials. “The system eliminates all human intervention into the filling area and provides an advanced aseptic assurance level,” says Li.
With RTU materials, Li notes that vial washing/depyrogenation, stoppers, and tooling sterilization are no longer required. The use of disposable technology reduces the risk for cross contamination, and thus also the sterility and particle risk. Aseptic media fill studies are also simplified due to the minimized need for intervention simulation. Combined with the smaller footprint, these factors help to reduce the cost of drug product operations, according to Li.
In addition, the system can handle a wide variety and sizes of contamination control strategies (CSS), such as vials, cartridges, and pre-filled syringes. “By design, the CCS formats reduce rejection rates caused by particles and other part defects that are more common in traditional rubber stopper and aluminum crimp seal configurations,” observes Li.
Key in-process and product release analyses with this system include the bioburden and concentration for drug products, the weight check for filling accuracy, and sterility test for drug products, Li notes. The weight check for filling accuracy is performed inline using an automatic sampling and weighing system included with the machine. Sterility and bioburden tests are performed offline in the quality-control lab.
Since the first good manufacturing practice run using the robotic aseptic filling line was completed in WuXi Biologics’ DP4 facility in July 2019, no environmental monitoring excursions have occurred, all five media fills passed with a 100% success rate, and 16 client quality audits revealed no critical findings. Through the end of Q2 2020, the company has successfully filled more than 50 batches of drug product with an acceptance rate of up to 99.8%.
“Since constructing and implementing the Vanrx SA25, we have been able to demonstrate its value for the industry with much improved aseptic assurance, flexibility, capacity, and reliability to support our clients’ complex drug filling needs, particularly in terms of reduced time to market,” Li asserts.
Because aseptic filling is a complex process, a holistic approach to validation and assurance of the quality of this critical operation is essential. “The establishment of a thoroughly designed systematic approach is key to the successful validation of aseptic processes, including fill/finish,” states Kurz.
As a result, building and validating a quality program for aseptic filling operations requires the support of manufacturing, engineering, and technical teams, as well as quality control, according to Peters. “All functions have vested interests in the proper execution of media fills and aseptic fill processes to ensure patients receive life-enhancing and life-saving medicines,” she observes.
Donovan comments that a high level of process understanding is fundamental to successful validation of aseptic filling operations and manufacturing a product that meets quality standards. Using tools like TrackWise (Sparta Systems), an automated tracking system to manage change control and manufacturing investigations; good manufacturing practices; and monitoring process performance through continued process verification are key, he adds.
“The most common failure modes include contamination resulting from human intervention and exposure of critical surfaces before and during filling,” Donovan continues. “Therefore, continued investment in personnel training and development and facility maintenance through preventative maintenance and calibration programs is important. Adopting a QbD approach also results in fewer defects, failures, and investigations, higher yields, and lower costs, all indicators of a well-controlled, managed, reliable quality process,” he states.
For Lacourt, it is important that everyone involved in aseptic filling operations understands that aseptic processes rely heavily on process protocols, personnel practices, equipment utilization, and facility design and controls. “It is the combination of these elements that ensures the exclusion of microorganisms from sterile processes, components, and products. It isn’t sufficient to have the best techniques for intervention if the equipment is not properly designed or the facility is not qualified to ensure contamination control,” she concludes.
Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.