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Industry experts discuss the need for stricter environmental controls, whether to incorporate single-use technologies, and areas for improved automation.
Packaging sterile drug products into sterilized containers via sterilization or aseptic processing continues to be both an absolute necessity and a challenge for the bio/pharmaceutical industry. But where there are challenges, there is room for innovation as well as room to grow.
“Aseptic processing is one of the most challenging manufacturing processes in pharmaceutical development,” says Robert W. Lee, PhD, president, CDMO division, Lubrizol Life Science Health, a contract development and manufacturing organization (CDMO) located in Bethlehem, Pa. and provider of clinical and commercial aseptic processing. “Sterile is sterile. It is binary.”
One of the reasons aseptic processing, specifically, is so challenging is due to a lack of proper training as well as a lack of comprehensive understanding of the techniques. This can then lead to regulatory intervention.
“In aseptic processing, a lack of understanding of the importance of aseptic techniques and one’s impact on the environment can lead to an array of complications and compliance issues,” says Simren Ahmadi, quality specialist, GMP, Lubrizol Life Science Health. “For example, just last year, FDA issued 25 483 observation forms in relation to aseptic processing. Virtually, all these observations were regarding poor aseptic operational practices that were put in place by the facilities.”
According to Ahmadi, to adopt better aseptic practices and minimize regulatory observations, organizations must change how they view aseptic processing. Namely, to look at it not as an operation, but as a culture.
“When a facility adopts an aseptic culture, personnel begin to understand the ‘why’ behind aseptic processing and their impact on the environment. Explaining that aseptic techniques and behaviors are critical to avoid contamination and produce a sterile product for a patient while illustrating the impact one has on the environment enables personnel to understand why good aseptic technique is so important,” continues Ahmadi. “This promotes more comprehensive risk assessments, validations, qualifications, etc. by taking aseptic processing into consideration, which in turn identifies weak areas of a process before complications or compliance issues arise. Additionally, promoting an aseptic culture allows personnel to develop an audit mindset and know what to look for when it comes to aseptic processing. Personnel can continuously look for areas for improvement through their daily job functions or by simply walking on the floor and have any compliance issues addressed internally.”
Nonetheless, whether an organization views aseptic processing and sterilization as a culture or simply as a necessary step in the manufacturing process, the need for either isn’t up for debate.
“Sterility is an obligatory critical quality attribute for parenteral preparations; sterility cannot be assured by testing, but by use of well-designed, validated, and controlled manufacturing processes. Most modern therapeutics are parenteral preparations that are not suitable for terminal sterilization; instead, aseptic processing, whenever feasible, in combination with sterile filtration, has to be pursued,” says Hanns-Christian Mahler, CEO, ten23 health, a Switzerland-based CDMO with a specialty in the development and sterile manufacture of complex pharmaceuticals, such as biologics.
To have sterile end products, environmental controls must be in place. Quality assurance (QA) departments have their work cut out for them to perform risk assessments. Many processes must be established and standardized, and all employees must follow those processes faithfully.
“[QA] departments ensure aseptic processing will work as intended by performing risk assessments on the locations, methods, equipment, and frequency for the aseptic processing that will be conducted,” says Christopher DeHart, director of quality, Lubrizol Life Science Health. “In-depth quality risk assessments identify the risks involved with the aseptic process to be conducted and determine what controls need to be put in place to minimize these risks.”
DeHart breaks down these controls further:
Rainer Glöckler, head of new technologies, swissfillon—a ten23 health company that offers a range of services for sterile filling and finish of liquid active ingredients—breaks down environmental controls into three relevant categories:
Joerg Zimmermann, VP of Vetter Development Service External Affairs, Vetter Pharma-Fertigung GmbH & Co KG—a CDMO specializing in the fill/finish of sterile injectables and headquartered in Ravensburg, Germany—stresses the importance of a functioning cleanroom system.
“Before we get to the aseptic operation, we must first ensure that we have a functioning cleanroom system that provides a controlled environment for safe production. This includes tight controls on temperature, humidity, and differential pressure,” says Zimmermann. “Of utmost importance is airflow management to minimize the contamination risk. Air flows are visualized during the qualification of the cleanrooms to ensure unidirectional flow from the ceiling to the floor, and from the core filling area to the background. This needs to be done in static and dynamic conditions.”
Another aspect that should be noted is the importance of a sterile, Grade A, ISO 5 environment.
“Aseptic processing should be executed in a classified space with minimum characteristics for particulate and microbial control, consistent with ISO 5,” adds Kenneth Laderman, PhD, manufacturing director, Eurofins BioPharma Product Testing, a laboratory that supports small batch sterile GMP manufacturing in San Diego, Calif. “Maintaining this classification will require a routine cleaning and environmental monitoring program as well as controls over gowning, material movement, and personnel movement.”
Lee adds that, in addition to an ISO 5 environment, it’s also acceptable to use a fully closed process in an ISO 7 environment. This is where the entire product contact pathway is sterilized using steam-in-place methodology. Afterward, sterile API and sterile-filtered excipients are added aseptically to the closed system and the remainder of the process is conducted aseptically.
When interviewed by Pharmaceutical Technology, Eurofins BioPharma Product Testing, Lubrizol, and ten23 health confirmed using single-use technologies in some of their aseptic processes. As with most things, there are both benefits and risks in doing so.
“Single-use systems [SUS] are advantageous, as they reduce the need for cleaning validation/verification activities for your process,” says DeHart. “In addition, the materials come certified sterile, reducing the need for a validated autoclave cycle for your processing equipment. In terms of a CDMO business model, the cost of the [SUS] can be passed to the client, enabling a cost-effective way to provide sterile manufacturing activities.”
Laderman states that Eurofins utilizes single-use technology for many product contact surfaces.
“As a CDMO, single-use technology facilitates the processing of multiple APIs within the same facility,” says Laderman. “In the absence of this technology, it would be necessary to execute a new cleaning validation for each molecule introduced into the manufacturing suite. By maintaining a single-use isolated system, the process is streamlined, decreasing time for project execution as well as turnaround time.”
According to Lee, Lubrizol uses SUS for small-volume sterile solution processing because this technology provides sterility assurance and flexibility as well as saves time. Lee adds that while SUS can be expensive, avoiding cleaning validation can lead to cost savings, depending on the application.
Meanwhile, Mahler at ten23 health states that the company uses single-use technologies for compounding/formulation down to the filling needle.
“[SUS] offer various advantages from a pharmaceutical perspective, including avoiding the risk for cross-contamination and avoiding related cleaning validation activities,” says Mahler. “However, [SUS] are a significant concern to us from a sustainability perspective, and we believe that biopharmaceutical solution providers should research new, more sustainable options.”
Companies should consider the following when using (or considering using) SUS in aseptic processing, according to Lee:
Single-use technologies and SUS seem to have simplified processes and provided an alternative approach to more traditional methods in the realm of aseptic processing and sterilization. But one of the key disadvantageous is the supply chain. Similar to Lee, Zimmermann shares that recent shortages related to the pandemic have revealed that when a single-use component, for example, isn’t available, production comes to a stop.
“There are some products where everything in compounding and in the liquid path is single-use, and we have others where it makes more sense to do a hybrid approach, with only the tubing and the filters being disposables,” says Zimmermann. “One thing that most people are not aware of is that the capacity for gamma-radiation, the method of choice for most [SUS], is under extreme pressure. This is causing companies to reconsider the processes on a strategic level. Another aspect that is coming into greater focus is the waste management of [SUS]. At the moment, the standard of disposal is incineration, which is not the most sustainable method.”
The greatest risk in aseptic processing is, of course, contamination, which can lead to a possible rejection of a batch, loss in revenue, product shortages, etc. And what is the greatest risk for contamination? People.
Both Zimmermann and Mahler state that the highest risk in aseptic processing comes from operators. Intense training can help to avoid contamination along with proper, sterilized gowns and testing the operators.
Laderman adds that well-designed systems for cleaning and air handling will minimize the risk as well as gowning procedures and training of personnel. Eurofins BioPharma Product Testing, specifically, uses a robotic, gloveless isolator to limit the product’s exposure to the operator.
In addition to the inherent risks that humans pose, there are other avenues leading to contamination. Potential causes for contamination, according to Ahmadi, can be anything from poor aseptic technique to equipment.
“[A] facility must have robust validations, qualifications, risk assessments, investigations, etc., as well as a robust aseptic techniques training program. These documents and programs must also be periodically reviewed to ensure they remain compliant,” Ahmadi says. “An organization must also ensure the facility design of critical areas can be easily cleaned and that personnel have the room and means to work aseptically. Additionally, [QA] should maintain a presence on the floor to promote good aseptic techniques and conduct walkthroughs of critical areas to ensure the facility is in good order and personnel are practicing good aseptic techniques.”
Like any part of the manufacturing process, aseptic processing has room to improve automation and has made significant progress in recent years.
“Automation requires flexibility, both in scale and duration of the function, while limiting the need for direct contact with the operators,” says Laderman. “Most automated systems are iterative by nature, as consumables utilized by the process will need to be resupplied. Decreasing the frequency of the resupply will minimize the chances for contamination.”
Laderman shares that Eurofins BioPharma Product Testing utilizes an automated robotic filler, which offers the lowest levels of extraneous particulate matter and the highest of sterility assurance. However, it’s dependent on the standardized nested vials and caps. Laderman believes that automation will continue to improve and be more readily adopted once additional vial types and sizes are available in standardized formats.
Similarly, when asked about opportunities for improved automation, Zimmermann points to the use of robots.
“Whatever can be automated, should be automated,” says Zimmermann. “The use of robots in cleanroom settings is increasing and constantly adding new tasks executed by robots. For us, this is not new, as we have been using robots since 1994. However, on new developments like the Flexi-cell that we are progressing with a partner, the robot does three distinct operations: set-up of the fill-line, the filling and stoppering process, and environmental monitoring. This makes the aseptic operation less risky and more robust. Automated environmental monitoring is considered for even more applications, but also remote troubleshooting via robot arms is being considered as well.”
Glöckler, on the other hand, looks to filling equipment without any glove intervention during aseptic processing as an area of improved automation. While the risk of contamination may be lessened, Glöckler adds that any problem in the isolator has the potential to impact process performance.
“Continuous online particle and bioburden testing replacing Settle plates, active air, and continuous particle measurement are in a development stage but still not accepted by authorities,” says Glöckler.
“Aseptic processing is better automated in that there is less human contact with the product, significantly lowering the possibility of contamination,” says Ahmadi, weighing in on the aseptic processing automation. “Automated aseptic processing removes the need for an operator to have close contact with the product and minimizes the number of operators needed in and out of critical areas. However, if automated aseptic processing is utilized, additional controls need to be put in place to ensure the equipment remains sterile. These controls include intervention procedures, cleaning validations, maintenance, etc. Aseptic processing is also better automated because it can produce more products in a shorter amount of time and minimizes the number of materials that need to be autoclaved. However, if the equipment is not functioning properly, there will be a loss of revenue in downtime.”
While we can’t banish humans entirely from the process floor, minimizing the risk associated with their presence is a major goal. Where the aseptic processing industry goes next, only time will tell. But it seems that single-use technologies and robotics will play a role in what’s on the horizon.
Meg Rivers is a senior editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International.
Vol. 46, No. 6
Pages: 16–18, 21
When referring to this article, please cite it as M. Rivers, “Automating Aseptic Processing Reduces Contamination Risk,” Pharmaceutical Technology 46 (6) 2022.