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.
1. EU GMP Annex 1
The final Annex 1 revision, published on August 25, 2022, proved to be a high point of discussion. Companies now needed to comply with the requirements no later than August 25, 2023, which was fewer than 100 days from the date of the conference.
It was surprising to learn through responses shared at the conference that organizations are still in the early phases of preparing a gap assessment and have not begun implementing remediation actions to ensure compliance by the deadline. For these companies, meeting all the requirements within the expected timeframe will be difficult. Knowing the clock is ticking and required implementation is imminent, companies are urged to identify the gaps and create a realistic remediation plan with tangible actions.
The interactive questionnaire session on this presentation revealed that 56% of the participants indicated their main source of information needed to comply with Annex 1 came from the company’s own subject matter experts. Another question referred to the top three Annex 1 topics companies still found to be subject to interpretation and where they felt further clarification from regulatory authorities would be helpful. Top of the list was pre-use post-sterilization testing (PUPSIT), followed by contamination control strategy and first-air principles.
The various regulators who took part in the session all emphasized the importance of using the principles of quality risk management (QRM) correctly, as it enables organizations to understand the characteristics of their products and their manufacturing processes, along with the facilities and utilities that support their manufacture.
It was highlighted that QRM is not intended to avoid good practices or Annex 1 expectations such as PUPSIT or to justify bad practices, nor is it to justify a predetermined outcome.
A solid risk assessment facilitates prioritizing and acting on the identified risks.
2. New Technologies
Annex 1 repeatedly emphasizes the need for companies to consider the use of appropriate technologies, such as restricted access barrier systems (RABS), isolators and robotic systems, to increase the protection of the product from potential extraneous sources of contamination. It also reiterates the use of rapid and alternative methods to detect potential contaminants in the environment and the product. This is not new to pharmaceutical sterile manufacturing, so expressing these expectations in Annex 1 should not come as a surprise. In 2004, the FDA published its final report, Pharmaceutical CGMPs for the 21st Century – a Risk-Based Approach, laying out the basis for science-based policies and standards to facilitate innovation. The guidance document recommends building quality into products through science-based facility, equipment, process and system design to ensure robust product protection.
Much of the 2023 PDA Good Aseptic Manufacturing Conference agenda covered topics regarding developments in new technologies, equipment and utilities, in addition to the use of new methods and innovative tools.
In 2018, approximately 50% of the aseptic filling lines in the EU and United States were of conventional design—a Grade-A filling enclosure with a Grade-B background that was manually disinfected and comprised open-door interventions, where the operator physically engaged with the critical Grade-A environment. Since then, an increasing number of companies have upgraded their existing equipment, availing themselves of RABS or isolator technology.
From the interactive questionnaire session, 31% of the respondents indicated that their organization planned to implement isolator technology in the next five years, with 20% specifying it would be done within the next year.
The first robotic-assisted surgery occurred in 1997, and the FDA approved the Da Vinci system for general robotic surgery in 2000. Since then, gloveless robotic systems have also emerged within aseptic filling as a more frequently seen technology. Options are available for open-isolator settings where automated systems or robots reduce the need for glove handling of certain process aspects like line startup and line clearance at batch end, in-process weight checks and completion of environmental monitoring, to name a few. The pinnacle is a design where robot technology fully replaces the need for operator intervention in a closed-isolator setting.
2023 PDA Good Aseptic Manufacturing Conference and 2023 PDA Site Visit at IDT Biologika
From May 23-24, an international trade gathering occurred at the 2023 PDA Good Aseptic Manufacturing Conference in Leipzig, Germany. The conference's primary focus centered around “Solutions for Implementation of the New EU GMP Annex 1 in Current Operations”, and it was met with great interest, particularly regarding the conference’s topics.
The 2023 PDA Good Aseptic Manufacturing Conference content was highly relevant for CDMOs such as IDT Biologika, as it offered solutions for the implementation of the new requirements. This first edition of the new conference format featured an additional, optional third day, which included a site visit to IDT Biologika in Dessau-Roßlau, Germany.
Due to the COVID-19 pandemic, the conference was given a complete overhaul, and the high level of trade interest, the avid discussions during the conference and the large number of participants confirm that the new concept of the conference was validated. Kerstin Wilken, PhD, from the development department at IDT Biologika, acted as conference co-chair of the Scientific Program Planning Committee and coordinator of the visit to IDT Biologika.
The combination of lectures on the implementation of the new Annex 1, the opportunity to submit questions to representatives of the regulatory authorities and the desire to interact with colleagues in association with a visit to a Contract Development and Manufacturing Organization (CDMO), such as IDT Biologika, exceeded everyone’s expectations.
“We registered 160 conference attendees. These came from 19 countries and a variety of different sectors. They included engineers, suppliers, consultants, pharma companies, as well as representatives of healthcare bodies. The conference took place in Leipzig over the course of two days and was accompanied by workshops. The supporting exhibition was fully booked, with 24 exhibitors. In addition, 50 people also registered for the site visit. This is a great success,” said Wilken, PhD. For IDT Biologika, this was a good opportunity to interact with an international audience and highlight its expertise.
The diverse aspects contained in Annex 1 were emphasized highly at the conference, consisting of the following:
- The implementation of regulations
- The changing of disinfectant
A varied range of other aspects of Annex 1 were examined, with great conversation and subsequent immersion in the respective know-how. “The site visit also turned out really well. Guests received a lot of input from our experts in the departments. During the one-day event, participants were able to visit five different stations in small groups, where they could gain an overview of the work of a CDMO, from media preparation to waste management. We had several groups guided to the individual stations by colleagues from the commercial department. “The IDT employees at the stations made intensive preparations for the visit. The visitors had a lot of questions. The efforts really paid off, because the guests gave us good feedback,” Wilken’s, PhD, concluded.
The next event will take place from May 15-16, 2024, and will follow on from this year’s agenda. Next year, we will also see another optional site visit to Syntegon.
About IDT Biologika
IDT Biologika is an innovative biotech company with a successful history of 100 years. Based on modern technologies and high levels of expertise, IDT supports customers in developing and manufacturing innovative virus vaccines, gene and immune therapy products, along with biologics that are employed worldwide as protection against diseases. German sites are the BioPharmaPark in Dessau-Roßlau and Magdeburg. In the United States, the IDT Corporation has a manufacturing site for clinical test samples in Rockville, Maryland.
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
- 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.
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.