The Bridge to Compliance with Annex 1 GMP, 11 DI and 15 Q&V and road to Pharma 5.0 and Sustainability

Conor Murray, Principal, 3dimension Cleanrooms, Head of Delegation for NSAI (Irish national standards body), Ireland

The latest Annex 1 is now a global document, as a collaboration between PIC/S and EMA, focused on QRM and a CCS (contamination control strategy).  It now completes the trio of GMP documents for sterile medicines, along with Annex 11 on Data Integrity and Annex 15 on Qualification and Validation.

This presentation will focus on:

• the fundamental importance of firstly understanding the detail of the process and what makes product quality,
• a gap analysis to previous GMP approaches,
• adopting new technology, including ARMM and airflow visualisation,
• integration of Annex 11 DI, and Annex 15 Q&V,
• link to PAT in Pharma 5.0 and Sustainability

to create a holistic approach to a CCS (contamination control strategy).

Contamination control in practice – From Construction Site to Manufacturing Excellence
Alenka Koblar, PhD, Quality assurance/Bio Injectables production, Lek d.d., a Sandoz company, Slovenia

When designing a new manufacturing site, the first challenge is translating the space you have into a layout that inherently protects the product: rooms must be arranged to define clear, segregated flows for materials, personnel and waste, so movement never increases cross‑contamination risk. From that foundation, utilities and media control are built into the design—water, steam and process gases are specified with quality attributes and hygienic distribution, while HVAC is engineered for stable pressure cascades, appropriate airflow patterns and zoning across cleanliness classes. These choices only work if the environment is cleanable and durable, so construction and finishing materials are selected to support effective cleaning and disinfection and minimize particle generation.
Special attention goes also to equipment (e.g filling lines), where product, environment and operator intersect; their layout, enclosure, airflow and interventions should be designed in a way to reduce bioburden and human‑factor risks.
Next step is upstream analysis how contamination could enter at every interface through the manufacturing processes—facility, equipment, utilities, material and people. Structured risk assessment (e.g., FMEA) is crucial to identify critical contamination control points and prescribe controls and responses from the start, compensating for the early‑phase reality that trend data are limited and cannot yet confirm the design’s performance.
Taken together, these decisions create a facility and process that embed contamination control by design, enabling consistent product quality.

Evolving Qualification Requirements Under Annex 1: A Case Study in Cleanroom Performance and Redesign

Meta Resnik, Global Aseptic Expert, Lek d.d., Slovenia

The 2022 revision of EU GMP Annex 1 introduced substantial changes to the qualification of cleanrooms, equipment, and supporting systems, shifting expectations from simple ISO 14644 compliance toward a comprehensive, risk‑based approach driven by the Contamination Control Strategy (CCS). These enhanced requirements have created significant challenges for newly established cleanrooms and added further complexity for existing facilities in aseptic manufacturing.

For sites originally designed under earlier standards, the revision necessitated a considerable increase in operational data collection based on identified risk areas. Although the resulting data, when evaluated in isolation, did not always provide meaningful additional insight, systematic integration of datasets, coupled with trend analysis and an in‑depth understanding of underlying processes, ultimately enabled the identification of new perspectives and opportunities for improvement.

Within the scope of this case study, it will be demonstrated how an observed adverse personnel environmental monitoring (EM) trend led to the identification of insufficient airflow visualization studies and ultimately to a cleanroom HVAC redesign, prompted by the revised expectations of EU GMP Annex 1.

CCS Blind Spots-Missed Risks in a Contamination Control Strategy
Ziva Abraham, Ph.D, Founder and CEO, Microrite, Inc. USA

Despite established contamination control strategies, organizations continue to face microbial contamination challenges. These issues often stem from inadequate risk assessments, ineffective investigations, and insufficient identification of critical control points. Effective contamination control requires a holistic approach, encompassing facility design through to product release. This presentation will highlight real-world case studies that demonstrate the importance of thorough risk assessments. Particular attention will be given to failed investigations of microbial contamination, especially mold, emphasizing the need to understand the contaminant’s nature, source, transmission, and proliferation risks.

 The importance and role of ISO (14644) and CEN (EN 17141) standards in the application of GMP Annex 1
Conor Murray, Principal, 3dimension Cleanrooms, Head of Delegation for NSAI (Irish national standards body), Ireland

ISO (the 14644 series) and CEN (EN 17141) standards play a key role in the practical and consistent implementation of the requirements of GMP Annex 1, as they provide the technical foundation for the design, qualification, operation, and microbiological monitoring of cleanrooms.

This presentation will focus on:

• importance of initial Qualification to demonstrate a state of microbiological control and CCS,
• reinforcing the adoption of new technology, including ARMM and airflow visualization,
• leveraging the ISO 14644 family of standards, in particular the latest -3 on Test methods, -4 on Design and -5 on Operations,
• update on the revision of the role of EN 17141, Microbiological Control, including ARMM and real-time BFPC (Bioluorescent Particle Counting).

Case study: How horizontal airflow in a robotic gloveless isolator was designed and verified to meet regulatory expectations using airflow visualization and CFD
Noël Long, B.S. Microbiology, Cytiva Isolators, USA
Katie Hay, M. Eng. Mechanical Engineering, Cytiva Isolators, USA

Isolator technology has predominantly been using vertical airflow for aseptic filling.  In this case study, we present the engineering and quality by design principles that led to the use of horizontal airflow and the advantages it provides for product protection. This robotic gloveless aseptic isolator design eliminates the main sources of contamination during aseptic filling operations with a unique tub decontamination and transfer system that ensures open containers are maintained at a working height within a flow of unidirectional airs that sweeps over and away from the critical areas.  We share the airflow visualization studies that used a proprietary blend of ‘smoke’ particles, custom manifolds and multiple camera angles and tell the story of how the smoke studies and CFDs informed the decisions for the airflow parameters, diffuser designs and environmental monitoring locations.

From Traditional Monitoring to Advanced BFPC & Airflow Visualization – Practical Case Studies Across Cleanroom Grades

• Nataša Štirn, Expert for Cleanroom Technology & Quality Systems, Klimer Štirn & Co d.n.o., Slovenia, President SCS
  Introduction & framework
• Agnes Krmelj, QA Manager, Lonstroff d.o.o., Slovenia
  Adopting BFPC and Airflow Visualization in Capping Manufacturing – Upgrading from ISO 5 to GMP Grade A
• Dražana Radonjić, Doctor of Biological Sciences, Head of Microbiological Laboratory, Labena d.o.o., BIA Separations CRO Laboratory, Slovenia
  From Traditional Monitoring to Real-Time BFPC: Practical Use of BioTrak in Cleanroom Grade C & B

The session “From Traditional Monitoring to Advanced BFPC & Airflow Visualization – Practical Case Studies Across Cleanroom Grades” provides a comprehensive overview of the transition from conventional environmental monitoring approaches to advanced Biofluorescent Particle Counting (BFPC) and airflow visualization techniques, aligned with current regulatory expectations and EU GMP Annex 1.
The introduction sets the framework for understanding BFPC and airflow visualization as complementary tools within a modern Contamination Control Strategy (CCS), highlighting their role in real-time risk identification and improved process understanding across different cleanroom grades.
A practical case study from capping manufacturing demonstrates the implementation of BFPC and airflow visualization when upgrading from ISO 5 to GMP Grade A, addressing challenges related to first air protection, critical zone control, and decision-making during process and facility upgrades.
The session concludes with real-world experience from microbiological laboratory operations, showcasing the practical use of BioTrak technology in Grade C and B cleanrooms, illustrating how real-time BFPC data enhances traditional monitoring programs, supports investigations, and contributes to proactive contamination control.
Together, these case studies provide valuable insights into the practical application, benefits, and limitations of advanced monitoring technologies across cleanroom environments, offering clear takeaways for industry professionals involved in cleanroom design, qualification, and operation.

Understanding Hydrogen Peroxide Vapour and its application
John Chewins, Scientific & Regulatory Director, Bioquell/Ecolab, United Kingdom

The presentation will deliver the fundamental theoretical concepts of the hydrogen peroxide vapour process and how rapid microbiological kill is achieved. The speaker will look at the use of hydrogen peroxide vapour systems within closed systems, related to the requirements of GMP Annex 1 and introduce the audience to regulatory requirements under the European biocidal products regulation. The presentation will look at the use of biological and chemical indicators in the validation of hydrogen peroxide vapour systems.
 
The presentation will deliver the following learning points:

1. Basics of hydrogen peroxide vapour processes
2. Use of hydrogen peroxide vapour in closed systems under GMP Annex 1
3. Understanding the requirements of EU BPR applied to hydrogen peroxide systems
4. Use of biological and chemical indicators in cycle validation

Cleanrooms Advanced HVAC Design – Update on New ASHRAE Cleanroom Design Guide
Vincent A. Sakraida, Chair TC 9.11 ASHRAE, Lead Mechanical Engineer, Olsson Engineering, USA

The seminar presents the ASHRAE TC9.11 Clean Spaces technical committee and its involvement in pushing forward innovation in Cleanroom technology and promoting the ISO 14644 family of “dashes” in Cleanroom standards.  Topics to be covered include how ASHRAE is leveraging the ISO 14644, IEST recommended practices and CETA guidelines, NEBB Cleanroom Performance Testing Standard, TC 9.11 is responsible for Chapter 19, Cleanroom design in the HVAC Applications Guide and the “How To” ASHRAE Cleanroom Design Guide. In particular, ASHRAE is giving detailed design guidance on the development of supply air flow calculation procedure to replace air change rate tables, removed from ISO 14644-4:2022 along with case studies on the application of IAO 14644-16, Energy Management.

Anticipating the reality through modeling: VR, AR, CFD and Digital Twin technologies in the project lifecycle
Pier Angelo Galligani, President and Co-founder of Techniconsult, Techniconsult, Italy
Andrea Daviddi, CDE Manager , Techniconsult, Italy

This presentation examines how Augmented Reality (AR), Virtual Reality (VR), Computational Fluid Dynamics (CFD), and Digital Twin technologies can support pharmaceutical facility project development, starting from a BIM-based approach. These tools are presented as enablers of an integrated and collaborative project delivery process rather than standalone solutions.
During the design phase, the combined use of VR-based design reviews and CFD simulations enhances stakeholder involvement while enabling early assessment of ergonomics and system performance through the simulation of critical parameters.
In the construction phase, AR supports on-site activities by enabling visual clash detection during installation, verifying correct asset placement, and providing objective, data-driven progress monitoring.
VR-based training for production and maintenance personnel can be delivered during non-operational periods, reducing time to operational readiness and decoupling training from site activities. This approach contributes to lower health, safety, and compliance risks.
The development of a Digital Twin further strengthens knowledge management, supports maintenance operations, and provides a unified decision-support environment for management teams. Properly structured data also lays the foundation for the effective adoption of current and future AI-driven operational tools.
Selected case studies will be presented to illustrate these concepts and their practical application.

Good and Poor Practices in the Design and Execution of Cleanrooms
Primož Vrtačnik, Project Engineering Investment Manager, Novartis d.o.o., Slovenia

The presentation covers general good and bad practices in the design and construction of cleanrooms, optimization during the operational phase, and frequent inspection findings identified during audits.

Smart HVAC design – Opportunity for Demand Based Contamination Control using Venturi Valves

David Rausch, Director of Strategic Partnerships / Business Development, Research, Healthcare and Clean Room Markets, Phoenix Controls, USA

Cleanroom applications such as battery manufacturing facilities, pharmaceutical production, and semiconductor fabrication all have one thing in common: the facilities they are made in use excessive amounts of energy and air. According to various sources, cleanrooms can use anywhere from 2-50 times more energy than non-classified rooms. Unsurprisingly, most of this energy use can be attributed to the HVAC system. Given the high value of the outputs of these facilities, there is often more emphasis placed on reducing risk over saving energy, and this is a valid concern for facilities owners. However, what if we told you there is a way to achieve both a high-quality product and improved energy management?

This presentation will provide you with the basic approach on HVAC and pressure control design strategies with a focus on the ISO Class Cleanrooms. Specifically, we will emphasize variable air volume control and demand-based ventilation for pharmaceutical fabrication plants.

Airflow Visualization in Critical Areas: Advancements in Standards and Applications

Bill Shade, M.S.E.E Johns Hopkins University, Microrite Inc., USA

A new ASTM standard titled ASTM E3379-25 Standard Guide for Critical Airflow Visualization has been published.

This guide was developed to provide best practices regarding Air Flow Visualization (AVS) in critical areas. It is intended to be read in conjunction with International Cleanroom standards (ISO 14644 family), the U.S. Food and Drug Administration (FDA), Eudra-Lex, PIC/S, and WHO requirements for airflow visualization, also referred to as “Smoke Studies.”

This presentation will address airflow visualization as referenced in these standards, regulations, guidance, and the new standard, ASTM E3379-25. The presentation will also discuss advanced applications, including in situ air pattern analysis of dynamic product path operation in Isolators.

Topics of Discussion Include:

• Terminology related to Airflow Visualization, definitions of First Air and Neutral Buoyancy.
• Procedural considerations
• Acceptance Criteria
• Types of Equipment Used for AVS
• AVS Equipment Requirements for Testing Isolators
• Manifold Considerations for Tracer Particle Introduction into the Critical Areas
• Recording and Documenting AVS Data
• Data Integrity
• Preparation for Airflow Visualization Studies

Designing Cleanroom Robotics Right: Qualification, Testing and Contamination Risk Management under IEST-RP-CC053.1 »Cleanroom Robotics«

Hasim Solmaz, Vice President of Innovation at Lighthouse Worldwide Solutions (LWS) and General Manager of its EMEA operations based in Turkiye

The growing deployment of robotics in cleanrooms reduces human intervention but introduces new contamination risks. Robotic systems are dynamic mechanical assemblies that may generate particles, disturb airflow, and create surface contamination if not properly designed and qualified. IEST-RP-CC053.1 (2024) provides a structured framework addressing contamination control considerations for robotics in cleanrooms and controlled environments.

This paper interprets the Recommended Practice from an implementation perspective, focusing on material selection, surface finish, lubrication management, cleanability, and airflow interaction under operational conditions. Emphasis is placed on in-situ qualification, particle emission during dynamic operation, impact on unidirectional airflow, and long-term mechanical wear.

Rather than summarizing the RP, this study translates its principles into practical risk management guidance aligned with contamination control strategies. When systematically applied, robotics becomes a controlled asset that enhances process robustness and regulatory confidence instead of introducing uncontrolled variability in modern cleanroom facilities.

Advanced HVAC Optimization for Pharmaceutical Cleanrooms – Predictive Control and Process Scheduling Approaches
Rok Prešeren, Ph.D, Advanced Control Systems & Automation, Metronik d.o.o., Slovenia

In pharmaceutical manufacturing, air quality in production areas is critical and must remain within regulated limits. Significant deviations can compromise product quality to the extent that entire batches must be destroyed. While different products require different production conditions such as temperature and humidity, all demand tightly controlled environments and properly treated air to ensure the required level of cleanliness.
To meet these requirements, HVAC systems continuously process fresh outdoor air and regulate temperature, humidity, pressure, and circulation, resulting in substantial energy consumption. A medium-sized production facility can exceed 10 GWh of annual energy use for air handling alone.
A key limitation of current HVAC control solutions is their reactive nature: they respond to changes after they occur rather than anticipating future system states. This leads to more frequent and aggressive control actions, increased mechanical stress on HVAC, and excessive energy consumption. This presentation discusses approaches to predicting future system behaviour, from simple models to AI-based predictive control, and addresses operational and business constraints of deployment.
Predictive HVAC control is also linked to production scheduling. Optimal schedules group products with identical operating regimes and adapt these clusters to daily and weekly variations in outdoor air conditions. The approaches are illustrated with practical examples.

Innovative solutions for transfer, filling and packaging of API substances in closed sterile environment
Tilen Ovniček, Project Engineer, Iskra PIO d.o.o.

Iskra PIO developed JetLoad High-Performance Isolator for Sterile Material Transfer, a unique solution for the sterile and safe addition of powdered raw materials into pharmaceutical processes with no risk of contamination. The high-performance system enhances process efficiency and ensures uncompromising final product quality. This innovation comprehensively improves isolator systems for sterile filling in the
pharmaceutical and biopharmaceutical industries. Iskra PIO also developed Aseptic powder filling isolator system, the innovative solution of a highly flexible isolator system represents an advancement in the technological processes within the pharmaceutical and biopharmaceutical industries. It solves the challenges of optimizing logistics and manipulation, ensuring a sterile environment for filling, and process efficiency. The unique system is a novelty on the global market and includes a greater number of innovative solutions.

Personnel – key factor in maintaining appropriate conditions in the production of sterile dosage forms

Boštjan Kmet, Deputy Head of Sterile and Non Sterile Liquid Products, Krka d.d., Slovenia

To establish conditions for sterile production, we need appropriate cleanrooms design, HVAC system that ensures proper air quality and airflow, utilities and equipment that will enable product manufacturing (transfer of primary packaging and raw materials, preparation, filtration, filling and sterilization equipment).

In addition to the above, it is important to note that the key contaminant in clean rooms is personnel. Points of consideration should include gowning procedure, behaviour, aseptic procedures, maximum number of personnel, performing of cleaning and disinfection, maintenance and microbiological monitoring.

The crucial point is proper training and qualification of employees and their awareness of how important they are in ensuring high-quality, safe, and effective medicines. Our training consists of different modules, through which personnel are educated from basic knowledge of microbiology to confirmation of competence with aseptic process simulation. We periodically review knowledge and skills to upgrade and improve their aseptic techniques.

Hana Prtenjak – SpaceDent: Contamination Control and Dental Procedures in Microgravity

SpaceDent is the first Slovenian student project carried out within the ESA Academy programme of the European Space Agency (ESA). The procedures were performed in a specially designed isolated experimental environment, which prevented the spread of particle contamination within the aircraft cabin and avoided unwanted interactions with other experiments. The results demonstrated that sufficient contamination control can be achieved even in microgravity, enabling safe performance of dental procedures. This opens new possibilities for expanding the range of medical and surgical interventions that could be carried out during future space missions.

ICCCS – Young Professionals Programme

The People Behind the Cleanrooms of Tomorrow – Betul Solmaz, Chair of the ICCCS Young Professionals Committee (IYPC)
Opportunities for developing an engineering career in Cleanroom technology abroad

ICCCS Young Professionals Programme (50 YP Initiative) connects the next generation of cleanroom professionals from around the world. The programme provides a platform for learning, collaboration, and knowledge exchange, where young experts work alongside experienced committee members to contribute to the development of cleanroom technology. Through mentorship, international cooperation, and shared professional values, the initiative helps strengthen the future of the global cleanroom community.

Academic paths in the field of cleanroom technology
University of Maribor – Faculty of Mechanical Engineering
University of Ljubljana – Faculty of Mechanical Engineering

National Institute for Bioprocessing Research and Training (NIBRT) is one of the world’s leading centres for education, research, and professional training in biopharmaceutical manufacturing and biotechnology. NIBRT offers academic programmes, specialized industry training, and applied research collaborations that support the development of highly skilled professionals in the biopharma sector. Through international collaboration with universities, research institutes, and industry partners, NIBRT enables knowledge transfer, talent development, and continuous professional training for both students and professionals already working in biopharmaceutical manufacturing.