Q&A on the Revised PDA Technical Report No. 22

The revised PDA Technical Report No. 22: Process Simulation for Aseptically Filled Products represents the culmination of over two-and-a-half years of dedicated effort by a team of experts from diverse backgrounds and geographical regions.

This collaborative endeavor brought together professionals with extensive experience in aseptic processing, contamination control, risk management and regulatory compliance from different product types and technology applications, ensuring the report reflects a comprehensive and globally relevant perspective. By drawing on the knowledge and experience from different regions and industries, we created a document that comprehensively addresses some of the industry’s practical shop floor challenges while complying with current regulatory standards. This article aims to provide readers with a preview of the key updates in this revised technical report.

What is the purpose of this revision?

While EU GMP Annex 1: Manufacture of Sterile Medicinal Products was certainly one of the driving forces for the revision, it has been more than 10 years since the initial TR-22 was published, and during that time, both the regulations and the technology within our industry have changed significantly. Thus, it was no surprise that many aspects of the technical report required updates and additional context to remain current to today's practices and needs. One example is the aseptic process simulation acceptance criteria.

A batch size-dependent number of contaminations in aseptic process simulations (APS) is no longer acceptable. Significant improvements have been made in the industry's best practices for aseptic processing. By virtue of a globally diversified team of experts, we ensured such regulatory changes and best practices are appropriately captured in this document. The revised report aims to reflect changes in therapeutics, technology, regulatory expectations and the industry as a whole. While the revised Annex 1 has had a significant impact, the revised technical report also reflects many other influences.

What are the new technology applications addressed in the revised TR-22?

One of the key updates of the revised TR-22 is the detailed elaboration on best practices for conducting APS across different sterile product types, such as solutions, suspensions, lyophilized products and dry powders, and incorporating new technology applications into each section. This section offers practical, up-to-date guidance that aligns with current regulatory standards, expectations and industry best practices in aseptic processing. As regulators increasingly encourage the adoption of advanced technologies, such as isolators, robotics and single-use systems (SUS), we recognized a growing need in the industry for clear, actionable guidance on conducting APS with these technologies.

The updated TR-22 addresses common questions like, "What different approach in APS applies to isolators or restricted access barrier systems (RABS) compared to conventional aseptic lines?" This and other such questions are answered comprehensively along with the scientific rationale that covers several critical areas like barrier systems (including isolators, RABS and blow-fill-seal technology), closed systems, pre-use post-sterilization integrity testing (PUPSIT) assembly, manual aseptic operations (with a specific focus on advanced therapy medicinal products [ATMP]) and SUS.

These updates reflect the industry's growing focus on risk management, contamination control and the use of cutting-edge technologies. By exploring these advancements, the revised TR-22 provides valuable knowledge for manufacturers looking to enhance their APS to meet the current industry benchmark and regulatory expectations.

Does this new revision address the "end of production or campaign APS”?

End-of-production (or “piggyback”) APS gained traction across the industry as isolators became more widespread. As confidence in using isolators grew, manufacturers started to feel more comfortable, increasing the number of product lots managed within a single campaign and the overall campaign length. With longer campaigns, the traditional approach of media fills for the entire campaign duration became impractical.

To address this, the concept emerged of revalidating a campaign by processing several batches and substituting the final product batch with an APS, thus introducing the piggyback APS. However—spoiler alert—while a piggyback APS plays an important role in the overall APS strategy, it is insufficient to fully validate or revalidate a line. This is primarily because a piggyback APS fails to adequately capture the critical operations required to set up the production line, install critical equipment and perform aseptic interventions.

Does this version provide any input with respect to the application of the concepts with real-world examples?

Several of the real-world examples that have been added are aimed at helping the reader see the application of the concepts laid out in TR-22 in a very practical format. They are there to help the reader put the applications of those concepts into practice, thus helping to facilitate the application in their specific scenario. The revised technical report outlines a valuable approach for establishing a risk-based model in ATMP manufacturing. It involves a recent adaptation of the Intervention Risk Evaluation and Management (IREM) framework. This model specifically breaks down interventions and assesses their associated risk, with particular consideration given to the manual processes involved in ATMP manufacture.

With the increased emphasis on risk assessment in the recent regulatory guidelines, is there anything new about risk assessment in the TR-22 revision?

The revised TR-22 significantly emphasizes risk assessment in alignment with recent regulatory guidelines, reflecting the growing industry focus on quality risk management (QRM). The new version incorporates a more structured and detailed approach to integrating risk assessment into aseptic processing. One of the key additions is the introduction of an appendix that provides real-life examples of how risk assessment principles can be applied to aseptic process design and simulation studies. This would help organizations better understand the practical implementation of QRM in their processes.

The report encourages a proactive approach, focusing on identifying and mitigating potential risks early through robust process design and controls rather than relying solely on reactive measures. Not only is there a section dedicated to risk management, but the concepts of risk management are also visible throughout nearly every section of the document.

How does this new document address the role of APS in contamination control strategy of an organization?

The APS is an integral component of a successful contamination control strategy (CCS), supporting both the validation of aseptic processes and the continuous monitoring and improvement needed to maintain product sterility and regulatory compliance. Annex 1 emphasizes that APS should not be viewed in isolation, thus ensuring that all aspects of aseptic production, including human interventions and equipment performance, are optimized to minimize contamination risks.

This revised technical report will provide considerations not only on how to appropriately integrate your APS into your CCS but also on leveraging the specifics of your CCS to develop the most appropriate APS for your facility. This is the fundamental expectation for companies to evolve and maintain ongoing improvements to these critical programs.

Are there any new simulation scenarios discussed in the TR-22 revision?

The revised technical report contains several new simulation scenarios discussed across various product types and manufacturing technologies. It is never possible to cover every possible permutation. Still, the revision aims to provide the foundational basis to support the user in risk-assessing their own individual applications.

Is there a bracketing approach in the case of multiproduct lines discussed in this document?

The revised TR-22 looks at bracketing approaches across various parameters including, but not limited to, container closure configurations, line speeds and product types. One of the aspects discussed is the case of different product formulations on a single line and speaks to some of the parameters to consider in those cases to create an appropriate bracketing strategy.

There is no universal answer, as the specifics will vary from line to line, but the guidance provided aims to allow the application of the concepts to create a scientifically sound and justified approach that can be implemented for each case.

Does this document address novel product categories like ATMPs?

The revised TR-22 provides guidance on APS strategies tailored for ATMPs, recognizing their unique manufacturing challenges, manual dependencies and requirements. It covers areas like manual aseptic operations and the use of advanced technologies, ensuring that the APS for ATMPs aligns with both regulatory expectations and industry best practices.

Are there any changes in the approach discussed in this document related to personnel training and qualification?

Employee training and qualification are crucial aspects of the CCS of any facility that manufactures sterile drug products. This is an area to which the industry needs to pay closer attention to ensure product and patient safety. The revised report contains an updated section dealing with training, qualification and periodic requalification for personnel who enter classified areas.

TR-22 aims to provide a holistic roadmap for the appropriate training and qualification of personnel involved in aseptic operations, up to and including their qualification during APS and the maintenance of that qualification over time. It discusses a phased approach, beginning with employee induction, followed by qualification for performing less critical tasks under supervision, advancing through various stages of training and qualification and culminating in the final qualification stage through APS. Additionally, it highlights the requirements for ongoing requalification to ensure sustained proficiency in aseptic operations, thus minimizing the potential risk of contamination.