2026 ISPE无菌会议监管座谈梳理附录1全球协调与无菌灌装问答

This year, the “Regulatory Panel Discussion: Annex 1 and Global Harmonization on Aseptic Filling” consisted of:

Oversight of External Manufacturing Networks

How should manufacturers relying on global contract development and manufacturing organizations (CDMOs) demonstrate adequate oversight and unified quality standards?

Answers:

Jackson (MHRA) explained that regulators expect a clear definition of responsibilities between marketing authorization holders and manufacturers, as outlined in the GMP reflection paper on marketing authorization responsibilities. He emphasized that companies must implement a robust supplier qualification program, covering both initial qualification and ongoing oversight of CMOs, suppliers, and service providers. Furthermore, structured communication and escalation processes between all involved parties are essential.

Friedman (US FDA) agreed, noting that regulatory expectations for strong supplier lifecycle management programs are well established globally. Two particularly helpful guidance documents are ICH Q9(R1) and US FDA’s guidance on contract manufacturing agreements.

Zimmermann complemented the regulatory view by highlighting that beyond technical requirements, successful collaboration with CDMOs depends on strong governance, trust, and long-term partnerships.

Assessment of Contamination Control Strategy (CCS)

How do regulators assess the maturity and effectiveness of a contamination control strategy (CCS) beyond documentation?

Answers:

Jackson stated that Annex 1 requires a holistic system that is continuously reviewed and improved. He emphasized that senior management holds ultimate responsibility for ensuring an effective pharmaceutical quality system and must actively support and resource it.

Pitts explained that inspectors assess CCS effectiveness through data, including deviations, trends, out-of-specification results, and monitoring outcomes. She noted that supporting evidence such as smoke studies, stability data, and corrective actions plays a crucial role in demonstrating system maturity.

Friedman underlined that CCS starts with making sound facility and equipment design choices. He added it must be treated as a lifecycle concept, continuously informed by process performance data and ongoing monitoring, demonstrating maturity through vigilance and adaptation.

Global Alignment of Annex 1 Interpretation

What steps are being taken to harmonize Annex 1 interpretation globally?

Answers:

Jackson explained that Annex 1 has already been harmonized through PIC/S, ensuring that global regulators apply the same core standards. He noted that additional work is ongoing, including the development of interpretation Q&A documents and training programs for inspectors.

Friedman echoed US FDA’s alignment with Annex I. [Note: Friedman[A1.1] was a member of the PIC/S Annex I Working Group that developed the guideline.]

Hydrogen Peroxide (VHP/BHP) Usage

Is there increasing regulatory pressure on VHP-based decontamination?

Answers:

Friedman clarified that there is no increased regulatory pressure. Instead, there may be more attention because VHP technology is now more widely used in the industry. He explained that observed deficiencies often relate to recurring decontamination cycle efficacy problems and deficient surface exposure.

Aseptic Process Simulations (APS)

Should APS focus on maximum interventions or representative interventions?

Answers:

Arigo explained that regulators expect interventions to be appropriately representative of actual commercial operations.

Friedman added that expectations depend on the system: more flexibility is permitted for APS protocol design for isolators, whereas non-isolator systems that employ extensive manual interventions require stricter adherence to worst-case simulation principles.

Pitts confirmed that inspectors will check whether those interventions conducted during commercial batch manufacture are actually performed during simulations.

First Air and Design Principles

Can the use of sterile components compensate for interruption of first air?

Answers:

Pitts stated clearly that violation of first air principles is not acceptable and often indicates a design flaw. She emphasized that risks must be mitigated through proper design, supported by smoke studies and environmental monitoring.

Friedman reinforced that both manufacturing equipment and the process should be designed to prevent such hazards.

Rogue Biological Indicators in vaporized hydrogen peroxide (VHP)

How should “rogue” biological indicators be handled?

Answer:

Friedman explained that isolated occurrences must be investigated as deviations. However, recurring issues or adverse trends often indicate insufficient robustness of the VHP cycle and necessitate corrective action. He stated that companies often modify equipment setup and configuration, or they optimize cycle parameters such as airflow, exposure conditions, and duration. He also mentioned how heat mapping studies can reveal variation that can influence micro-condensation.

Environmental Monitoring in Advanced Systems

Can environmental monitoring be reduced in robotic or advanced aseptic systems?

Answers:

Arigo stated that some level of environmental monitoring will always be required. However, reductions may be acceptable if justified with robust scientific data and supported by process understanding.

Friedman confirmed that regulators are open to appropriate risk-based reductions for robotic isolators, while emphasizing that monitoring should still focus on critical risk areas.

Grade A Air Supply Terminology

Does the concept of “Grade A air supply” create confusion?

Answers:

Jackson clarified that Annex 1 provides a clear definition: Grade A supply delivers filtered air meeting Grade A particle limits but does not require full unidirectional airflow or full monitoring. He cited vial crimping as a typical application.

Friedman confirmed agreement with this example as an appropriate application of the Grade A air supply concept from the US FDA perspective.

Isolator Setup and Gowning

Are isolators treated similarly to restricted access barrier systems (RABS) in terms of gowning requirements?

Answers:

Pitts explained that operators must wear full sterile gowning when setting up isolators. She emphasized that personnel are a major contamination source and must be controlled accordingly.

Dual-Mode Isolators

What evidence is required when switching isolators between containment and aseptic modes?

Answer:

Friedman stated that such a proposed transition would seem to require extensive qualification and, if found appropriate, ongoing verification data would be essential to provide evidence of control due to the fundamentally different operational conditions. He noted that more detailed case-specific information would be needed to enable meaningful regulatory evaluation and feedback.

Sterile Connection Devices

Are expectations for single-use systems (SUS) and sterile connection devices becoming stricter since publication of Annex 1?

Answer:

From the US FDA perspective, Friedman explained that sterile connection devices reduce risk but do not eliminate it. Failure modes such as operator errors or defects still exist, and therefore Grade A air supply is generally expected when performing such connections. He added that some inspections had found significant SUS integrity issues.

Airflow Visualization Frequency

How often should airflow visualization be repeated?

Answers:

Pitts stated that there is no fixed frequency. Instead, requalification should follow a risk-based approach and be triggered by changes in equipment, processes, or facility conditions.

Jackson added that periodic review and effective change management are essential in determining appropriate intervals.

Brownfield Facilities

How can legacy facilities justify incomplete Annex 1 compliance?

Answers:

Pitts explained that companies must demonstrate a robust CCS supported by comprehensive risk assessments. She highlighted possible mitigation measures such as increased monitoring, use of isolators, or additional contamination controls.

Jackson stressed that companies should already have implemented improvement plans and demonstrated transparency during inspections.

Common Misunderstandings of Annex 1

What are the most common misconceptions?

Answer:

The regulators noted that some companies still rely on outdated processing approaches and misunderstand the intent of risk-based implementation. Risk assessments must be objective and science-driven rather than used to justify pre-defined conclusions.

Gap Between Expectation and Practice

Where are the biggest gaps in implementation?

Answer:

The regulators identified remaining gaps in areas such as automation, material transfers, and reduction of manual interventions. They highlighted that Annex 1 now clearly endorses increased automation and reduced direct operator interfaces with the aseptic processing line as core design objectives.

Indicators of true contamination control strategy (CCS) Understanding

What demonstrates genuine understanding of contamination control?

Answers:

Friedman stated that two key indicators are the proper application of quality risk management principles (ICH Q9) starting at the design stage, along with strong systems for ongoing monitoring and continual improvement.

Jackson added that CCS should be treated as a dynamic, evolving system driven by data and scientific understanding.

Innovation in Aseptic Processing

What is the US FDA’s position on new technologies such as robotic isolators?

Answer:

Friedman emphasized that regulators are highly supportive of robotic isolators. He noted the next-level contamination risk reduction that can be afforded by the technology, given the repeatability enabled by highly capable automated equipment. He stressed that robust design, understanding failure modes, software validation, and a strong maintenance program are essential prerequisites.

Final Key Message

What is the main takeaway for manufacturers?

Answer:

Jackson concluded that manufacturers are fully responsible for product quality, and inspections represent only a sampling exercise. He noted that differences between inspectors are due to different observations, not different standards, and emphasized that all regulators apply the same guiding principles.

Also see the related blogs summarizing the opening and closing plenary session presentations by FDA’s Rick Friedman and John Arigo, respectively.

Looking Ahead: The 2026 ISPE Annual Meeting & Expo

ISPE’s largest conference of the year, the 2026 ISPE Annual Meeting & Expo, will feature an extensive lineup of regulators and industry experts, with a Global Regulatory Town Hall planned for Wednesday, 21 October. The event will run from 18–21 October, and takes place in Washington, DC, United States.

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Disclaimer

The views expressed by the panelists are their own and do not necessarily represent the official positions of the US FDA or MHRA. This article is a summary of the session prepared from the conference recording and has not been vetted by the agencies cited; questions and answers have been edited for clarity.