Seven Key Takeaways from PDA’s Good Aseptic Manufacturing Conference

The 2023 PDA Good Aseptic Manufacturing Conference brought together industry experts to share efficient and sustainable solutions for the implementation of EU GMP Annex 1: Manufacture of Sterile Medicinal Products. Drawing nearly twice as many attendees than initially expected, the May 23-24 event in Leipzig, Germany, offered a fully packed program that addressed myriad topics related to aseptic manufacturing.

Various industry experts, along with current regulators from the European Union (EU) and U.S. FDA, gave a mix of presentations, sharing their knowledge and insights on developments within the arena of aseptic manufacturing. Each session culminated with an interactive question-and-answer period that allowed participants the opportunity to ask the panel of experts about the topics they presented.

Attendees were also afforded the opportunity to speak to various vendors in the exhibition area to learn more about industrial advancements in new methods, innovative tools, and emerging developments in new technologies, equipment and utilities.

Above all, the conference allowed attendees to share their interpretations, challenges and possible solutions for the compliant implementation of the new revision of Annex 1 with their peers from the industry. The event was deemed a success based on the high level of interaction and engagement with presenters and the number of questions asked during the interactive questionnaire sessions.

Key Takeaways

The latter comes with the big advantage of completely removing human interaction from the process. Still, regardless of the extent of automation and technological capabilities, it also comes with some challenges. The first the challenge would be regarding the design of robotics and their movements. Annex 1 emphasizes that Grade-A conditions should be ensured with first-air protection, preventing obstruction of the path of the unidirectional airflow. This principle also applies to an automated process. Replacing old equipment with robots could even worsen the practices of aseptic assurance. Correct design and adaptation of the robot’s movement to prevent moving parts above the critical process are important to protect first air. The maintenance of unidirectional airflow must be demonstrated and qualified across the whole of the Grade-A area by air visualization studies. Using computational fluid dynamics studies is a helpful technology in designing robotic systems and for visualizing the impact such a system has on the airflow within the isolator before physically designing the robot.

The second challenge is any automated system or robot will only perform as well as it has been instructed. Process understanding and programming the system to perform activities in the correct sequence at the exact right time can be time-consuming, with many trials and errors before getting it right.

Finally, the design must allow for full decontamination in the isolator and prevent the risk of product being exposed to surfaces that may not have been decontaminated during operations?

Such methods can work and are accepted by regulators when implemented correctly. This was demonstrated by examples, such as semiautomated filling of ATMPs and glove-filling of drug products, including automatic installation of the filling path.

This indicates that the opportunities are endless with much more to be expected as technology evolves.

4. Real-Time Microbial and Particle Detection

Having robotics perform environmental monitoring within an isolator is one aspect, but it still requires an incubation period before the final results are obtained. The same applies to sampling and testing of utilities, mycoplasma testing of biological products and sterility testing of the final drug product; these all require incubation of samples to detect microbial contamination.

European legislation has already expressed its expectation for the use of modern technologies. Article 23 of EU Directive 2001/83 states, “After an authorization has been issued, the authorization holder must […], take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods.” Section 9.28 of Annex 1 further emphasizes “that suitable alternative monitoring systems such as rapid methods should be considered to expedite the detection of microbiological contamination issues.”

Rapid microbiological detection systems can be an option to consider in reducing the time to result, with different technologies available from which end users can choose. Applications using ATP-bioluminescence, measuring changes in such metabolic activities as pH and CO2, polymerase chain reactions and DNA sequencing are examples of the gamut of available technologies. Their suitability depends on what one wants to achieve with some critical points to consider:

• Time to result
• Sample preparation and overall complexity
• Limit of detection
• Presentation of results, CFU or units
• Destructive or nondestructive
• Known and accepted technology
• Commercial availability and support
• Reference standards available
• Test capacity
• Validation
• Comparability to the compendial method
• Cost of equipment and tests

Presentations were given where real-time monitoring of air quality within an isolator was applied in support of conventional air sampling using biofluorescent particle-counting. The equipment used was capable of generating results for total-particulate counts and viable-particulate counts based on the measurement of fluorescence signals emitted by viable particles. The benefits described were that results are presented in real time, which allows for a direct reaction to an alarm. As no media is used, there is also no requirement for changing samples, thus, preventing necessary interventions.

Annex 1 presents the maximum permitted microbial contamination levels in colony-forming units (CFU), expects the manufacturer to scientifically justify the limits applied, and, where possible, correlate these to CFUs. Challenges presented themselves with the real-time air sampler as results were reported in auto-fluorescent units (AFU) and not in CFUs. Study results showed that AFU counts were significantly higher than CFU counts. Besides the false positives due to interfering factors, the higher levels of AFU were explained by the fact that all living microbes emit intrinsic fluorescence. However, this does not mean these microbes are culturable, as they could be damaged, dormant or stressed. Furthermore, the broad limitations of the traditional environmental-monitoring media, like tryptic soy agar (TSA) and sampling methods, may hinder the microbes’ cultivability.

As Annex 1 encourages the use of rapid microbial methods (RMMs) and science is evolving with emerging technologies that detect the presence of microorganisms differently than traditional cultivation methods, there is a clear requirement from all parties involved—end users, manufacturers and regulatory bodies—to stay informed about developments in the world of RMMs. In an open dialogue, all involved can educate another about the benefits RMMs can bring but also appreciate the limitations and gain an understanding of the differences compared to the traditional methods. This will help adjust expectations and clarify the requirements for both the industry and regulatory agencies when considering the implementation of an RMM.

5. The Human Factor

Despite all the promising new technologies that are already available and those to come in the future to help the manufacture of sterile medicinal products, the human factor remains one of the most important elements in the success or failure of manufacturing quality products.

A solid training and qualification program for both new and existing personnel is one of the cornerstones for achieving compliance and delivering safe products. Many of the training programs we see across the industry focus on the need demonstrate compliance to relevant procedures and regulations. Focusing on the compliance element alone brings the risk that personnel are merely following the procedure, demonstrating the “how” and “what to do,” but not understanding the “why.” Embedding scientific thinking in a training and qualification program stimulates the trainee to think about the why-element, as it provides the reasons for executing manufacturing steps in a certain way, for example, why a specific temperature must be maintained and the importance of wearing cleanroom clothing of the right size. It allows personnel to understand the scientific reasons behind procedures and what the impact could be in the case of deviations. It motivates personnel to challenge the status quo and, therewith, encourages continuous improvement.

6. Equipment Design and Commissioning

Early involvement of operating personnel, along with the team of engineers, in designing and testing a new filling line can potentially prevent many issues and setbacks. What might look good on paper, meeting all technical specifications, is not a guarantee that the end users can work with what was designed and agreed upon. Once a line is built, making fundamental changes is difficult, even impossible. However, operators must live with what is available from that point forward. This can lead to suboptimal situations that pose a risk to the process, for example, when gloves on the isolator are positioned incorrectly, making it hard to reach all areas. It can potentially result in noncompliance situations when environmental sample locations for total particulates and viable particulates are randomly selected and not based on the actual process risks and QRM principles, leading to regulatory observations.

When end users and other personnel with specific technical and regulatory expertise, such as microbiologists, are involved from the beginning and have their input taken seriously, it can prevent longer-term issues. It also promotes ownership and allows for the early development of sound procedures based on gained experience rather than theory.

7. Augmented and Virtual Reality

Besides the emerging manufacturing technologies described, new applications in delivering training programs are also surfacing. Augmented reality (AR) is one of these; it guides the operator through a step-by-step workflow, where the person is learning by doing the actual tasks. Rather than just reading and following a procedure, the new trainee actually operates a virtualized machine, where the trainer can follow the activities via a computer screen and give direct feedback.

With virtual reality (VR), situations can be created where the trainee is asked to perform specific tasks, for example, transfer materials within an isolator from Grade A to Grade B. The training software allows for a realistic presentation of the impact the operator has on the environment and direct feedback can be given. The benefits of both AR and VR are that the training is done in a safe environment, where there is no risk to the actual cleanroom, equipment or product, and the trainee can build confidence and competence before participating in a real qualification.

These digital innovations can be tailored to a company’s unique processes or equipment, giving a realistic picture of the actual situations that person is going to face. This approach does not only cover the “how and what” aspect, but also the “why,” as it instantly shows the impact if something goes wrong. Applications were demonstrated where video technology was used in support of risk-profiling ATMP manufacturing, with the entire process dissected into small individual tasks. These microtasks were analyzed further, identifying what could go wrong during each individual step. Subsequently, work instructions were written with an emphasis on these risks, while providing clear instructions on how to perform the task and what to avoid. The video technology also helped in the development of the training module, where the video recordings demonstrated the correct ways of working and the areas of risk.

Summary

As per Annex 1, organizations are expected to have their facilities, equipment and processes appropriately designed to increase the protection of the product from potential extraneous resources of contamination. Considerations for using new technologies must be made to reduce the contamination risk or increase the detectability should such contamination occur. Many options are already available, all with their own benefits, challenges and limitations that must be considered and understood before employing such technology.

Whether at the design and implementation phase of new equipment or the routine operation of a well-established process, the human factor remains inherent to the process and must not be overlooked. A robust training program is paramount to providing personnel with the right qualifications and experience to manufacture a safe, quality product. A well-designed program promotes scientific thinking and provides personnel with the “why” behind the processes and procedures. Technological advancements are seen in both the manufacturing environment and personnel training and are expected to be considered to improve product quality and, ultimately, patient safety.