Abstract

16, October 2024

PLENARY SESSION – STANDARDS & REGULATIONS

Update and Progress on ISO/TC209 WG2 towards a new ISO 14644-20
Conor Murray
ISO TC209 NP on “Biocontamination control” was registered in the work programme of ISO/TC 209 in 2022. This New Work (NP) item was proposed as a revision of ISO 14698, Parts 1 and 2 published in 2003. The intention of the NP is to create a new ISO 14644-20 standard that will replace the existing EN ISO 14698 Parts 1 and 2:2003 and the EN 17141:2020. The subject of applied microbiology to Cleanrooms has always proved challenging as the applications are so varied and there are varying levels of regulations and industry standards and guidelines. WG2 has met 12 times since WG2 started in October 2022, 5 of which were hybrid. WG2 SMEs are well represented by Microbiologists or Applied Microbiologists, and they are the driving force in the work group in terms of technical content and practical applications. This is a complex subject with different priorities and applications across the globe, and SMEs have strong opinions. As a result, progress has been slow. There has been plenty of debate over how prescriptive the new -20 should be and whether to follow the inclusion of informative guidance on specific applications, which is in the EN 17141:2020 standard.
This paper will share where there is consensus around scope and the priorities in the working group. The presenter will discuss some of the challenges and roadblocks around the inclusion of level of detail on environmental monitoring and specific application guidance.

Impact of the Paradigm shift in GMP regulations on ‘Connecting the Dots’ in Contamination Control
Drinkwater James L.
The revision of EU GMP Annex 1, publication of PICS Annex 1 (increasing international relevance), revision of ICHQ9(R1) QRM, and introduction of ICH Q12 on Product Life Cycle strategies has generated a paradigm shift in GMP regulations with a Risk-based, Proactive, and Holistic approach to medicinal and therapeutic product manufacturing. Through Annex 1 revision, the requirement for a contamination control strategy (CCS) has facilitated ‘Connecting the Dots’ in Contamination Control. The application of a systematic set of controls with a documented narrative on the approach taken to contamination control in product manufacturing has a focus on the collective effectiveness of control measures that provide improved assurance of product sterility. This presentation will focus on experience and impact of the new regulatory paradigm.
1. Overview of the Paradigm shift in GMP regulations and considered impact over a Product Life Cycle (ICHQ12).
2. Learning experiences from Annex 1 CCS preparation and application of QRM (ICHQ9(R1)) in ‘Connecting the Dots’ in Contamination Control.
3. Considering ICHQ12 ‘Established Conditions’: ECs as manufacturing environments subject to Contamination Control and how the ‘Dots’ are connected through Classification, Qualification, APS, Routine monitoring (EM and PrM), and re-qualifications over the product Life Cycle.
Perspective on the future following the paradigm shift in GMP regulations.

Cleanroom operations control program
Agricola Koos
ISO 14644-5:2004 provides guidance on cleanroom operations. In the new ISO 14644-5, which is in preparation (CD in 2023, DIS in 2024), operations control programs for proper cleanroom operation are developed. The intended operation of a cleanroom must be part of the requirements for a cleanroom (ISO 14644-4:2022). It must be implemented when the cleanroom becomes operational.
Cleanroom use should be described in operations control programs on personnel management (cleanroom clothing, changing, entry and exit, and training), cleaning, entry and exit of goods, maintenance, and monitoring. Reference is made to ISO 14644-18 on cleanroom suitability of consumables.
In the new ISO 14644-5, the topics that should be addressed in operations control programs are described. The goal is to keep air and surface cleanliness levels for particles and chemical substances within the required limits. It is recommended to prepare a set of draft operations control programs when setting up the requirements of a cleanroom. Then the facilities necessary for proper operation can be implemented. Cleanroom installation and operations control programs must deliver the required cleanliness levels. The effectiveness of all measures can be demonstrated by monitoring.

Beyond ISO TR 14644-21 – dealing with airborne particle sampling challenges in the field
John Hargreaves
ISO TR 14644-21 was published in August 2023. The Technical Report format (not a standard), was chosen to provide easy, timely access to established consensus on airborne particle sampling techniques, so as to remedy difficulties in understanding current ISO 14644 parts 1 & 2. TR21 explains the basis of these standards, providing a rationale for addressing specific requirements in the field, e.g. some of the new EU GMP Annex 1 requirements for airborne particle sampling.
We found that many users were not aware of basic long-established considerations for robust airborne particle sampling, that are no longer detailed in the current ISO standards. Furthermore, the fundamental differences between classification and monitoring, which are expressed in the standards, are not taken into account in some regulated applications, leading to unrealistic demands.
The TR reviews recognised sources of error, to be assessed and managed in the context of various sampling situations, in relation to the quality requirements of the application.
To illustrate how to assess sampling systems, a decision tree provides a step-by-step approach.
For those systems presenting a high risk for large-particle loss, the TR indicates that further work is necessary to rethink and optimise the system. This paper provides information and feedback on how users have engaged in engineering optimisation of challenged sampling lines, especially in barrier technology uses.

PARALLEL SESSION – CLEANROOM DESIGN, OPERATION AND MAINTENANCE

Product Oriented Contamination Control
Koos Agricola
In many applications of contamination control the critical product must have a central place. Analysis of machining, cleaning, assembly and testing steps in the production flow is necessary to find the optimal process flow. In a product cleanliness strategy the steps where to clean, where to shield and where to implement clean controlled environments can be determined. In a product analysis the functional surfaces are determined. The functional surfaces are the vulnerable surfaces when exposed to the environment. The maximum amount of contamination is determined by the impact on the product function. A risk assessment helps to determine the critical locations and to quantify the contamination that must be prevented. For each step where the vulnerable surface is exposed, the contamination latitude can be determined. This information can be used to set limits for air cleanliness, particle deposition rate limit and surface cleanliness levels.
Product Oriented Contamination Control (POCC) is a method that is developed in the VCCN about 25 years ago. Implementation of VCCN Guideline 12 on Product Cleanliness, ISO 14644-2:2015, 14644-9:2022 and 14644-17:2021 on air cleanliness with respect to particles particles make POCC useful in the application of ISO 14644-4:2022 and 14644-5.
Ventilation efficiency: the impact of the temperature and velocity of the incoming air and internal heat loads
Leonello Sabatini
The analysis starts from the experimental results achieved at the time of verification of the two-flow descriptive model in an experimental cleanroom with symmetrical distribution of the air introduced. The data showed the theoretical validity of the model and the dependence of ventilation efficiency on the flow rate and thermal conditions. Thermal conditions that influence the inductive motions generated by the primary air entering the chamber itself. The temperature spectrum investigated at the time was limited as the purpose of the measurements was the analysis of the flow reversal. By expanding the data collected at the time, we will further investigate the influence, in the variations in ventilation efficiency, of the thermal differentials that are triggered in the transition between heating and cooling conditions. The simulation will be performed in the same test chamber used at the time, expanding the investigation to more internal sampling points.
Use of CFD simulation to optimize ventilation effectiveness in cleanrooms – case study
Lapo Galligani – Toni Valente
This work explores the application and strengths of numerical simulation techniques, specifically Computational Fluid Dynamics (CFD), in supporting the design of a pharmaceutical cleanroom and its ventilation system. The study is related to an ancillary room supporting the new production department for injectable anesthetic drugs at the Pierrel facility in Capua. The room is classified as Grade C according to EU GMP and characterized by a non-unidirectional air distribution. Computational Fluid Dynamics (CFD) simulation focused on maximizing the ventilation effectiveness provided by the air distribution system, in order to improve airflow uniformity and eliminating – or at least minimizing – areas with poor air flow distribution Special attention was given to calculating the expected recovery time in various points of the room; in fact this parameter can be used to assess the cleanroom’s attitude to react to a localized contamination event and CFD simulation can preliminarily anticipate it from the design stages. The importance of using CFD simulation is thus highlighted even in cases where air distribution is not unidirectional. The results obtained through CFD were then validated in the field through experimental tests.
Ventilation effectiveness in practice
Frans Saurwalt
One of the parameters of the equation to calculate the required supply airflow volume in a cleanroom, basing it on the contamination source strength, is the associated ventilation effectiveness.
In ISO 14644-4 this factor is indicated as 0,5-0,8 as good starting point. There is, however, a method of assessing existing configurations of supply diffusors, ceiling or low extracts and various specific air volume flows per room. This is done by evaluating the recovery time test (ISo 14644-3), usually performed This provides an interesting picture on the actual and local ventilation efficiencies as practically achieved and can form a good basis for new designs and the calculation of the required supply airflow volume to meet the required cleanliness levels based upon source strength.
Experimental and Computational Study of Upflow Cleanrooms
Takahiro Ishino
Optimizing airflow patterns is important for energy conservation in cleanrooms. The airflow patterns are strongly influenced by air supply and return configurations. This study experimentally and computationally compares five airflow types: downflow, filter unit upflow, fan filter unit upflow, displacement ventilation, and ceiling supply and return . In the downflow type, air was introduced through ceiling fan filter units and returned through perforated raised floor panels. In the filter unit upflow type, air was supplied through perforated raised floor panels and returned through perforated ceiling panels. In the fan filter unit upflow type, air was supplied by underfloor fan filter units and returned through perforated ceiling panels. The experiments involved three different indoor heat loads, and the number of air changes per hour varied from 17 to 106. As there were few particles larger than 5 µm, no significant differences were identified in the experiments for particles of this size. The fan filter unit upflow type had the lowest concentration of particles larger than 0.3 µm at 1.1 m above the floor in all the experimental conditions. This concentration was reduced by up to 65% compared to the downflow type. Computational fluid dynamics results agreed with the experimental data.

PARALLEL SESSION – BARRIER TECHNOLOGY 

Meeting the challenges of H2O2 Bio-decontamination with innovation in rapid validation methods
Kate Marshall
Enzyme Indicators (EIs) have been extensively discussed within publications and conference presentations as a rapid validation tool for providing instant and quantitative feedback, of H2O2 bio-decontamination efficacy. The process of H2O2 Bio-decontamination validation and what steps are important to ensure H2O2 bio-decontamination efficacy is understood, repeatable and robust remains varied within the industry, being reliant on individual Pharmaceutical manufacturing company strategies. So how does the EIs bring value to this process? Learn how the phases of H2O2 Bio-decontamination process, from design through to requalification are being conducted with the inclusion of EIs via case studies within the industry. The objective of the presentation is to provide a detailed, practical and case study driven presentation on what the validation lifecycle of H202 Bio-decontamination looks like with the inclusion of Enzyme indicators to ensure H2O2 bio-decontamination efficacy is understood, repeatable and robust.

Discover the Power of Biological Indicators: Unveiling the Science Behind Ensuring Impeccable Bio-Decontamination in Isolators
Maria Luisa Bernuzzi – Federica Straforini
Discover the Power of Biological Indicators: Unveiling the Science Behind Ensuring Impeccable Bio-Decontamination in Isolators. In the realm of cutting-edge Barrier Technologies like RABS and ISOLATORS, Annex 1 has focused on a critical aspect: the bio-decontamination process. Within this process, the validation of sporicidal agents decontaminating the interior of equipment stands as a pivotal step. Enter Biological Indicators – the precise “instruments” to assess the efficacy of sporicidal processes. But what exactly are Biological Indicators? They are more than just spores inoculated onto a substrate and housed in a specific container; they are the tools of validation, to assist in the development of the bio-decontamination cycle within a BSP isolator. These indicators possess unique characteristics for their crucial role in the validation process. From the supplier’s certificate of analysis to their strategic placement within the isolator, each step in harnessing Biological Indicators is infused with precision and scientific methodology. The selection of these indicators involves an intricate application of basic principles, proper usage of D-values, and crafting a meticulous strategy for equipment validation.

Gloveless Robotic Filling Line How to Meet Industry and Regulatory Requirements
Julian Petersen
In August 2023, the pharmaceutical industry underwent a significant transformation with the implementation of the new Annex 1. This pivotal update necessitates industry-wide compliance with its stringent requirements. A central focus of Annex 1 is the Contamination Control Strategy (CCS), a comprehensive framework designed to amalgamate various control measures. This presentation elucidates the advantages of adopting a quality by design approach for an aseptic filling line, specifically examining the profound impact on the CCS. Through the lens of a gloveless filling line, the session underscores the practical implications and benefits of this approach. While regulatory adherence remains paramount, the presentation delves beyond the surface, exploring the profound implications of gloveless fill and finish systems on the future of manufacturing. By navigating through the intricacies of compliance, the industry gains valuable insights into optimizing operational efficiency and ensuring product quality. The case study of a gloveless filling line serves as a tangible illustration of how cutting-edge technology aligns with regulatory demands and anticipates future manufacturing trends. The Contamination Control Strategy outlined in Annex 1 serves as a linchpin in ensuring the integrity of pharmaceutical manufacturing processes. By converging diverse control measures into a unified framework, the CCS becomes a cornerstone for maintaining product quality and patient safety.

Design of isolators for aseptic fill-finish in extreme environmental and containment conditions
Giacomo Guidi
In the current scenario of injectable products and related aseptic fill-finish lines, it is increasingly common to have to deal with configurations of the isolated solution and of the related ventilation systems where the environmental conditions in which the pharmaceutical product is handled are subject to temperature and humidity requirements outside standard ranges. An oxidant-free atmosphere may also be required for the isolator – either by creating an inert atmosphere (from which oxygen is completely removed), or by avoiding even minimal residues of hydrogen peroxide upon decontamination completion in the isolated area. Finally, it may be necessary to implement high containment strategies for the management of a high-potent product or for products implying a major biological risk. Implemented and qualified system solutions are presented capable of successfully addressing these scenarios. These production lines can have a filling area configured for low humidity production of cold-dispensed products (2-5°C) with a risk of condensate formation on direct contact parts, or for hot production, where the product requires an ambient temperature above 40°C. The issues addressed include the management of Grade A isolators with a unidirectional flow obtained by creating a completely inert atmosphere (pure nitrogen without oxygen) and how to create a ventilation system and related HVAC with nitrogen recirculation. Peculiar high containment solutions (one-pass) are also presented.

Airflow Visualization Studies: The Impact of Annex 1 on Sterility Assurance
Luca Calisi
Due to their expanded, central role in the new Annex 1, airflow visualization studies like Smoke Studies and Computational Fluid Dynamic (CFD) studies, have become one of the key aspects of a contamination control strategy (CCS) for companies. The importance of these studies is not limited to the qualification of clean rooms and clean air equipment, but if properly executed, they can also be used for other evaluations, such as the definition of the environmental monitoring plan, the training of personnel, and the specification of the positions of biological and chemical indicators for the validation of the VHP cycle. But what does “properly executed studies” mean? There are several requirements that must be met not only to comply with regulatory requirements, but also to generate a scientifically-sound study that allows for a careful examination of airflow patterns and any related risks. Smoke studies thus become not only a visualization and recording of air flows but a real analysis tool: a window on the hidden risks of our processes. For this reason, the figure of Sterility Assurance has a key role and must participate in the design, execution, and interpretation of the results using a Quality Risk Management (QRM) approach when necessary. This presentation will explor all these aspects with a particular focus on the interpretation and use of the information generated by these studies that can be used to build a holistic and effective contamination control strategy.

PARALLEL SESSION – MICROELECTRONICS AND ASSOCIATED TECHNOLOGIES

Study – The semiconductor industry in the context of the European economy
Udo Gommel
The global chip shortage keeps hitting the headlines: Supply problems with new electronic systems (cell phones, cars, production facilities, etc.) show us how dependent our modern society has become on semiconductors. The entire economic development depends on computer chips. Various studies have already examined the chip shortage from different perspectives. However, the effects on mechanical and plant engineering have not been taken into account. This presentation, accompanying the study “The chip shortage – opportunities for mechanical and plant engineering in Europe”, which was commissioned to Fraunhofer IPA by the German Engineering Federation (VDMA e.V.), is intended to close this gap and highlight the effects of the chip shortage on mechanical and plant engineering.
The results of this study are an important step in preparing the mechanical and plant engineering industry in Germany and Europe for future challenges: Measures must now be taken to strengthen essential parts of the global supply chains in Germany and Europe. There is sufficient potential for this: for example, know-how in chip design and production facilities. Further opportunities are offered by the implementation of innovations from numerous fields of research that help, for example, to improve material selection, production plant design, wear behaviour, precision and cleanliness or to avoid contamination.

A holistic approach for a large Wafers Fab. An Italian case study
Angelo Colleoni, Francesco Romano
The global chip shortage in the past years have shown how dependent are manufacturing industries, and in consequence everyone’s life, from semiconductor sectors. The aim of this paper is to treat from an holistic point of view the entire process of a green field EPCM and TCV process of a large 18 inches silicon wafers Fab in northern Italy. When dealing with silicon wafers, the role of contamination must be declined into different facets depending on the treatment and the processes to which the components undergo. Airborne cleanliness level, molecules concentration, water or electrostatic charges in the air are few of the key contamination parameters to keep under control in a pilot line ready to be switched into a mass production line. Process flow path for personnel and products are recognized to be one of the main source of cross contamination which may lead towards product defeats and therefore their logistics will be discussed. The paper will explain the steps, the actions and the technology approach used in order to maximize production and to minimize contamination and energy consumption in a sector where the high energy density usage factor leads towards an holistic optimization of the entire Fab instead of the single local process delivered by a tool or process line. The monthly chip production cannot be any more considered the leading KPI target to achieve if not well coupled and balanced with environmental, cost and logistics indexes.

Design essentials for future ready Micro/Nano Cleanrooms
Eric Stuiver
Over the last decades scientific and technological developments have pushed miniaturization, resulting in devices with dimensions on micro, nano and pico scales (Moore’s law). At the same time, abilities to direct and control the assembly of application specific biomolecules have emerged. Nowadays research is increasingly focused on the amalgamation of these two trends bringing us into the world of bionano-motors, sensors and personalized medicines. These miniaturization and amalgamation trends drive new, more stringent requirements for research laboratories and/or production cleanrooms. Key challenges include particles, vibrations, electromagnetic interference, airborne chemical contamination and temperature control. The planning and design to meet these extremely stringent conditions leads to ever more complex and costly cleanrooms.
In this presentation both the technical and financial impact of miniaturization and amalgamation trends on laboratory and cleanroom facilities will be discussed. Case studies introduce solutions on how to balance technical complexity with financial challenges. Lastly, a perspective will be presented how science and new technologies can drive us into future proof nanotechnology facilities.

Study on the Regeneration Method of Cation Exchange Resin for Treating Trace Level Airborne Molecular Contaminants
Wai Hoo Foong
Cation exchange resin (CER) is widely used in water treatment to adsorb ammonium ions in water. After adsorption saturation, it can be regenerated and reused. Trace levels of ammonia in the air of semiconductor cleanrooms can be treated through chemical filters, where the medium is made of two layers of non-woven media with granular CER embedded within the media. Generally, this type of filter is disposable, and discarded filters will be incinerated. CER cannot be collected from traditional designed chemical filters, nor can it be directly immersed in acidic solutions for regeneration. The main purpose of this study is to design a CER recyclable filter medium for treating trace levels of ammonia in semiconductor cleanrooms. This study evaluated the effects of different regeneration methods on the initial removal efficiency of 10ppbv ammonia and the adsorption capacity of 10ppmv ammonia, as well as the outgassing of CER after regeneration. The results showed that using hydrochloric acid solution and dynamic regeneration had the best regeneration effect, with at least 5 regenerations possible. The initial removal efficiency of regenerated CER for 10ppbv ammonia gas is greater than 95%, and the adsorption capacity of 10ppmv ammonia is restored to over 90% of the original CER. After multiple regenerations, the mechanical strength of CER did not show significant changes, and the outgassing met the requirements for semiconductor cleanroom use.

The NOA clean room facility for a large scale production of silicon detectors
Lucia Consiglio
Nuova Officina Assergi (NOA) is a semiconductor production facility realized at Laboratori Nazionali del Gran Sasso (LNGS), commissioned and operational since 2023. It is a clean room of 420 m2 divided in two controlled experimental areas with a reduced radon concentration. A larger area has been equipped of auxiliary plants providing utilities such as compressed air, vacuum, ultra-pure water, gas and liquid nitrogen. This area is mainly devoted to the assembly and test of large arrays of Silicon-based devices operated at cryogenic temperature. A second a smaller area but with a more sided ceiling has been conceived for the assembly and set up of large parts of detectors. The first area has been equipped with cutting-edge technology packaging machines and dedicated set ups and instrumentation for testing and qualifying the photosensor modules with the related electronics. The NOA infrastructure has been also designed to be compatible with the installation of a Rn abatement system that in perspective would make NOA a unique infrastructure for the packaging, test and assembly of photodetectors in a Rn free environment. The current goal of NOA until the end of 2025 is to accomplish the production of more than 10000 Si photodetector modules for the DarkSide-20k experiment. This result will represent an important milestone for the DarkSide-20k collaboration but also opens new frontiers for synergies with the research groups interested in the technologies inside this clean room.

PLENARY SESSION – HEALTHCARE 

Environmental Microbiological Monitoring Strategies
Laura Boschi
For aseptic processing that takes place in clean rooms, a key evaluation aspect is environmental monitoring, which must address both viable and nonviable particles.
Viable and nonviable particle values must be within the limits set by the guidelines, depending on the grade under consideration.
As for microbiological contamination, it is necessary to have defined an internal sampling plan, including air and surface monitoring using air samplers, settle plates, and contact plates. This plan must indicate the frequency of sampling, as well as their locations. Continuous monitoring is required during critical operations where the product is
exposed to the environment. Surfaces and personnel should be monitored after critical operations.
The locations of the sampling points must be defined in advance through risk analysis tools, aimed at assigning a Risk Priority Index (RPI) to each point identified based on factors both related to the plant/facility (presence of HEPA filters, return grid, doors, etc.) and the processes in place within the classified areas (transit of material, personnel, etc.).
From the analysis of the results obtained, it is possible to identify the most critical sampling points to be monitored routinely, and which will be evaluated when performing trend analysis.

Product safety and OOS (out of specifications) management
Monica Gunetti
The quality, safety and efficacy of the Advanced Therapy Medical Products (ATMPs) and compliance with the Good Manufacturing Practises (GMP) should be ensured for all ATMPs, regardless of whether they are produced in a clinical trial or industrial setting. Nevertheless, according to GMP guidelines for ATMPs, it is necessary to recognize a certain level of flexibility, above all in a clinical trial setting. To this purpose the ATMPs manufacturer should to implement, using a risk based approach, all the measures that are most appropriate for the peculiar characteristics of the manufacturing process and of the product. In fact the manufacture and testing of ATMPs requires specific challenges and strategies to ensure a high level of quality, considering the specific manufacturing process, the limited batch sizes and the inherent variability of the starting material. One of the biggest challenges that a manufacturer of ATMPs must consider is the possibility to start the production from fresh biological starting materials, as well as the possibility of releasing fresh finished products (DPs) without having obtained the results of all the release tests. In this context, a robust risk analysis and process and quality control test validation are important to guarantee safety and efficacy of ATMPs, in addition to a rapid management of deviations or out of specification (OOS) that could impact on the release of the DPs, which for some patients are the only remaining therapeutic options

Technical and Regulatory challenges of “Point of Care Manufacturing”
Andrea Urciuolo
Some innovative products, like ATMPs, but also blood products, 3D-printed small molecules, may have very short shelf-lives, or they may need to be highly personalized, so have to be manufactured on demand when the patient is present, in a health care facility, or close to it.
For these reasons, the strong need for a new decentralized production system has emerged.
The Industry and Regulatory Authorities are evaluating the advantages of decentralized production in Point of Care, which involves smaller production and flexible volumes in multiple locations, depending on the real need, also encouraging the development of personalized medicine.
Along with the opportunities, just as many technical and regulatory challenges are being identified.
The safety, quality and effectiveness of the products manufactured at the Point of Care must be guaranteed, but there is a need for a certain flexibility and new strategies in a context different from the traditional one. New strategies are also necessary from a technological point of view: How to guarantee aseptic processing in a hospital context? How to prevent risks of contamination and mix up in a healthcare facility where, ideally, different medicinal products can be manufactured for different patients?
The aim of our presentation is to bring to attention the issues, both regulatory and technical, that FDA, MHRA and EMA have started discussing over the last year, with some possible solutions that are being evaluated.

Automated compounding of non-hazardous drugs
Giuseppe Zucca
L’allestimento di preparati galenici magistrali (prescrizione del medico per specifico paziente) è un’attività rilevante in ambito ospedaliero ed è regolamentata dalle Norme di Buona Preparazione (NBP) della Farmacopea Ufficiale. La Farmacopea Ufficiale stabilisce che siano attivati una serie di controlli, quali la stabilità chimico-fisica del farmaco, la compatibilità dello stesso con il diluente ed il contenitore finale, il controllo quantitativo che può essere effettuato con diversi metodi. La gravimetria rappresenta l’opzione preferibile per tempistica, costi e precisione.
Queste attività di controllo (spesso non codificate e introdotte negli ospedali) presentano criticità e difficoltà organizzative di non facile soluzione e vengono svolte principalmente da personale infermieristico sottraendolo alla primaria attività di assistenza e causando una non rigorosa gestione del rischio clinico.
La presentazione riguarda un dispositivo che, attraverso l’automatizzazione del processo, garantisce la tracciabilità e il controllo di tutte le attività legate all’allestimento di preparati galenici magistrali.
Esso ha dimensioni e peso ridotti ed opera all’interno di un ambiente ISO5 autonomo. Integra innovazioni coperte da tutela brevettuale e consente di ridurre l’intervento manuale, minimizzando l’errore umano e i conseguenti rischi per la salute del paziente e dell’operatore nonché gli sprechi di specialità medicinali ad alto costo, diminuendo in conseguenza l’impatto ambientale.

Updating the SIFO Standards for galenics in oncology: reporting results from SIFO-ASCCA collaborating group
Costantino Jemos
The lack of internationally recognized regulatory technical guidelines on healthcare establishment (only PIC/s PE10/04 is available), combined with a very heterogeneous organizational and socioeconomic landscape led to a great variability in the quality levels required for aseptic preparation units in hospitals among Europe, resulting in significantly different levels of quality assurance in different contexts and introducing elements of lack of planning in the design and definition of required specifications for preparing facilities. However, there are documents with varying degrees of adaptability to the hospital setting. Among these, in Italy, there are the Standards for Galenics in Oncology of the Italian Society of Hospital Pharmacists (SIFO), published in 2016 and cited by the AIFA GCP Inspectorate as one among the reference documents. The purpose of the work is to review and update the SIFO document by incorporating new available document references, including the new Annex 1 of the GMP and the new edition of the ISOPP Standards.

17, October 2024

PLENARY SESSION – SUSTAINABILITY AND INNOVATIVE APPROACHES

Sustainability Ambition: Carbon Net Zero and Net Nature Positive
Ilaria Lo Presti
GSK has committed to work towards a net zero, nature positive, healthier planet, with ambitious goals set for 2030 and 2045. As a healthcare company, we can contribute to tackling both the causes and effects of climate change. We know that the twin crises of nature loss and climate change are linked and that action on nature is a critical part of achieving a net zero future. So, our nature plan is interdependent with and supports our commitment and pathway for a net zero impact on climate. Human health relies on the fundamentals of nature: clean air and fresh water. Nature loss has a range of negative impacts on health, for example, reduced air quality increases the incidence and severity of respiratory diseases, and habitat degradation and deforestation are increasing the risk of new human pathogens and pandemics. To protect human health and get ahead of disease, we need to protect nature. The presentation will aim to share the approach GSK is taking to achieve the 2030 targets with a specific focus on its own pharmaceutical operations. A snapshot of a number of case studies on climate and nature showing successes and progress within the constraints of highly regulated facilities. The healthcare sector has a dual role to play in getting ahead of this challenge.ases, and habitat degradation and deforestation are increasing the risk of new human pathogens and pandemics. To protect human health and get ahead of disease, we need to protect nature. The presentation will aim to share the approach GSK is taking to achieve the 2030 targets with a specific focus on its own pharmaceutical operations. A snapshot of a number of case studies on climate and nature showing successes and progress within the constraints of highly regulated facilities. The healthcare sector has a dual role to play in getting ahead of this challenge

Energy saving and decarbonization in a new biopharma manufacturing facility
Pier Angelo Galligani – Giorgio Amato
Energy efficiency and reducing the carbon footprint in a industrial facility align with best practices to support the “2030 Agenda for Sustainable Development” launched by the UN in 2015. While all 17 Sustainable Development Goals (SDGs) are crucial, sustainable design focuses on emergencies linked to climate change and preserving natural resources. Indeed, the life science industry’s energy footprint is relevant, due to substantial air conditioning needs for regulatory compliance, energy consumption in processes like steam sterilization, and the production and distribution of clean utilities.
The CO2 footprint, a key contributor to climate change, depends on energy and power generated within production facilities, supplied from external sources and energy consumption across all the company’s value chain (Scope 1, 2, 3 – GHG Protocol).
This work outlines energy efficiency in the project of a recently established pharmaceutical facility for the manufacturing of biological-based injectable products. Emphasis was placed on HVAC systems and industrial and clean utilities. Various simulation techniques (dynamic energy simulation, process simulation, computational fluid dynamics (CFD)) were extensively applied. The impact of these design solutions was compared to traditional plant solutions as a baseline, following the LEED protocol. The results show significant reductions in environmental impact and a notable return on the increased investment compared to baseline solutions

Energy Optimisation and Regulatory Alignment in GMP Cleanrooms – application of the New ISO 14644-16 to the new Annex 1
Klemen Skrlec – Natasa Stirn – Conor Murray
The emphasis in energy reduction in HVAC and Utilities in Cleanrooms is currently addressed from purely an Engineering perspective. There are many possible ways to reduce the energy footprint BUT they leave the Quality and Regulatory assessment to the end user. The real challenge in Life Sciences today is to apply a holistic approach and focus on Quality/Regulatory Affairs alignment and energy optimisation. This must be based on integrated EM Expertise, based on an analysis of both Non-Viable EM and Viable EM data to predict the new Cleanroom HVAC operating point and performance, that maintains product quality metrics and patient safety. This requires a very high level of integration of GMP Cleanroom expertise and capability, in conjunction with both Life Science Facilities Engineering and Manufacturing Operations. Advance engineering techniques and expertise in Airflow Modelling, Airflow Visualisation, real time Airborne Particle counting and real-time Biofluorescent counting (BFPC and AFUs), coupled with an analysis of traditional EM CFU based data are used to demonstrate the effectiveness and regulatory alignment of the planned energy optimisation measures. This presentation will focus on and provide a case study and experience from a user’s perspective in addressing the requirements of Quality and external regulatory compliance.

Advances in sustainable solutions at Life Science Facilities
Keith Beattie
As life science cleanrooms are some of the most energy intensive spaces and many operators are striving towards low/zero carbon operations, it is becoming clear that these high intensity spaces are an economic barrier to achieving the goal of decarbonisation. For decades, the approach to cleanroom ventilation has remained unchanged. Airflow provided to the space remains at a static level, with no regard for activity in the space, particle generation rate or the contamination challenge at any given point – missing a significant opportunity for ventilation rate reduction. This leads to excessive energy use when not required to safely maintain the critical conditions. Utilising a dynamic ventilation approach that embraces modern particle counter technology, dynamic cleanroom control now allows a facility to react to the particle generation rates within a cleanroom space and only provide the required airflow depending on this demand. This paper will use real-life data from the world’s first commercial implementation of this concept at a life science GMP regulated facility to demonstrate how this technology performs from a quality and compliance standpoint, as well as the associated, significant energy reduction

Case study on reuse/recycle of rain water in a pharmaceutical facility
Lilian Amaral
At Novo Nordisk, water is a fundamental resource for production and processes. Site Montes Claros is in a water-scarce region and the availability of water is a challenge in this region.
To address this challenge, the Site in Montes Claros built a rainwater reservoir to increase water availability for operations. The reservoir has a capacity for using 80 million liters of rainwater per year, which is equivalent to the annual consumption of 6060 families annually.
The plant for water treatment comprises a raw water storage tank with sodium hypochlorite dosing, an automatic microfiltration system, an ultrafiltration system, a UV lamp system, and an ultrafiltered water tank.
Physio-chemical and micro analysis are performed to ensure the potability of the water according to local legislation and WHO guidelines. The water that meets the potable standard is then subjected to the same purification steps already used in the purification of the potable water supplied by the external water provider.
The rainwater reservoir is approved by the local health authority. For approval, besides a technical visit to challenge the robustness of the system, it was required to demonstrate that the treated water is free from hazardous contaminants to human health, such as pesticides, heavy metals, among others.
By using this water source for our production process, we were able to reduce our water consumption by up to 12% in 2023 and aim to reduce it by 40% during normal rainfall periods.

Critical issue of pharmaceutical waste management within the broader framework of achieving a net zero waste approach and embracing circularity principles
Ringa Samah
The overarching goal of the conference is to address the critical issue of pharmaceutical waste management within the broader framework of achieving a net zero waste approach and embracing circularity principles.
This entails delving deeply into various strategies aimed at reducing, reusing, and recycling waste materials across the entire pharmaceutical supply chain, from production to quality control.
to achieve this objective, the conference will facilitate collaborative discussions and knowledge-sharing.
This involves a comprehensive examination of waste reduction, reuse, and recycling strategies throughout the pharmaceutical supply chain. Our approach will entail fostering collaborative efforts to establish circularity, beginning with waste mapping to outline methodologies and outcomes, participative workshops to facilitate engagement and share outcomes, and insights into pioneering practices capable of converting waste into new resources, such as solvent recovery.
the conference will also aim to foster a collaborative effort among stakeholders to develop holistic solutions for pharmaceutical waste management that align with sustainability goals and promote circularity in the industry.
Through collective action and innovative approaches, we strive to create a more sustainable and environmentally responsible pharmaceutical sector.
Participants will depart with tangible examples of waste reduction, material recovery initiatives 

A Greener Semiconductor Industry Challenges & Opportunities
Reinier Richters
Semiconductor technology is essential for enabling a sustainable future but introduces many important environmental challenges.
Manufacturers and production facilities are on a continuous search for sustainable solutions. Addressed towards the pressing need for sustainable practices in the semiconductor industry for net zero. There are plenty of opportunities and challenges in the industry which companies as Deerns can leverage to contribute to a Green Semiconductor Industry.
In the past semiconductor companies have focused on addressing the chip shortage and directed their energies into increasing supply. Many end customers are asking their suppliers, including semiconductor companies, to step up their efforts to reduce greenhouse-gas (GHG) emissions to achieve net-zero carbon emissions along their entire supply chain. Some semiconductor companies have recently set more aspirational emissions-reductions targets, but getting the industry to net zero will require more comprehensive action.
Measures towards net zero are reduction direct emissions (scope 1) through abatement and replacement, improved electrical energy efficiency and clean energy (scope 2) and leveraging the supply chain (scope 3), such as use of raw materials, chemicals and gases, to reduce their scopes 1/2/3.
On a view case studies best practices will be presented in the field of decarbonization/Energy Efficiency, water conservation and waste reuse/recovery including a look ahead to future developments

PARALLEL SESSION – CLEANROOM DESIGN, OPERATION AND MAINTENANCE

Integrated approach HVAC design and commissioning
Carlo Magni
The correct design of an HVAC system is tested during the star-up and commissioning phase. That’s why during the design it is necessary to take into consideration and to foresee all the possible problems that will be encountered during the start-up of the HVAC system: in this way the duration of the commissioning phase shall be reduced, and the correct balancing of the HVAC systems shall be more easily achieved. In addition to that, it is also during the design phase that all the measurements and precautions that will allow a better and easier operability and maintenance of the HVAC systems throughout their life cycle shall be foreseen. A good knowledge of the design basis and design process shall improve the commissioning life cycle, since it helps to solve the unpredictable events and problems that however shall occur during the start-up of the plants. The report shall explain how an integrated vision between the design and commissioning represents a win-win approach, and so allows to reach a successful achievement.
The correct design of an HVAC system is tested during the star-up and commissioning phase. That’s why during the design it is necessary to take into consideration and to foresee all the possible problems that will be encountered during the start-up of the HVAC system: in this way the duration of the commissioning phase shall be reduced, and the correct balancing of the HVAC systems shall be more easily achieved. In addition to that, it is also during the design.
The advances in Hepa Filtration equipment to improve test & validation efficiency and accuracy on your site
Micheal Feldtmann
HEPA is the acronym for “High Efficiency Particulate Air”-filter or sometimes referred to as“High Efficiency Particulate Arrestor”. The HEPA filter is a type of mechanical filter. It works by providing a barrier in the form of very fine fibres that trap practically all particles. HEPA filters are not a recent innovation, they were developed by the American Federal Government in the early 1950s. Now they are widely used as a protective and containment measure in all the industries which deal with hazardous contaminants or highly sensitive processes like the Nuclear , Biosafety , HPAPI , Emobility , Pharma and the Hospital industry to name a few . We know that the most important feature of an air filter is its efficiency, which is a measurement of its ability to remove airborne pollutants, such organic or inorganic particles and gases. Other essential properties of a filter include pressure drop and dust holding capacity. To measure these properties, the air filtration industry needs regulations to ensure that filter testing is performed consistently and reliably. These regulations help us to classify HEPA filters in different classes.
Bridging the gap between construction and operations & maintenance
Chris Delaney – Andre van Tongeren
In the life cycle of cleanrooms and associated controlled environments a lot of time is spent on design and construction. Sometimes there is a contradiction as on the one hand you have a construction team trying to build and hand over a facility and on the other operations & maintenance planning to operate and run the facility. Seldom this is a smooth transfer from the building phase to operation phase and this gap leads to a slow start up and a lot of problems.
In this presentation we are looking at these two distinct phases through the lens of facility management with the aim of bridging the gap. From the authors experiences of being involved in some of the largest cleanroom construction sites across Europe we aim to join up the dots to have both a successful construction and a successful operational startup. One of the main objectives of the presentation is to demonstrate how to “get it right first time”. The presentation also looks at the differences and similarities between a Semiconductor start up and a Biotech start-up. This dual track presentations will dive into how building cleaning is complementary to the building process and how maintaining clean is related to technical maintenance with the overarching goal of cleanroom performance throughout the lifespan of a cleanroom. Furthermore, it aims to demonstrate how the ISO 14644 body of standards can be used as a basis in support a successful transition from build phase to operational phase.
Maintenance strategies for cleanliness critical environments – Fast setups, high efficiency, cost-minimized
Udo Gommel
In sectors of industry with cleanliness requirements, the tiniest amount of contamination is sufficient to cause high reject rates. Such contamination may result in faulty microchips, space probes or optical lenses. To avoid this, the related production and assembly steps are conducted in a cleanroom. The construction of classic cleanrooms is mostly cost-intensive, stationary and time-consuming.
A new type of mobile cleanroom system is flexible, stable, transportable and offers a fast, local clean environment to suit individual requirements. The system offers defined cleanliness classes from 1 to 9 according to ISO 14644-1. For the first time, a cleanroom on demand is now available to companies and research institutes that can be erected when and where it is required to keep products and systems clean. In addition to the protection of selected contamination-critical areas, particle-generating processes can also be separated. The simple construction principle enables individual solutions to be installed within an hour. But even space-intensive solutions of up to approx. 500 square meters can be implemented in just a few days.
Research on Humidity Control Using a Desiccant wheel inside EFEM (Equipment Front End Module)
Seong Cheon Kim
Developing methods to reduce manufacturing costs and increase yields in the semiconductor production process is a task. With the trend towards semiconductor miniaturization, the requirements for cleanliness have become more stringent. The EFEM is used in the pre and post stages of the manufacturing process to supply and transport wafers within the FOUPs. Clean conditions within the EFEM are maintained by Fan Filter Units (FFU) at the top, which remove particulate and gaseous contaminants. However, the typical humidity level in cleanrooms (45% RH) can cause oxidation of the metal wiring on wafers in some processes due to moisture. This study focused on developing an ultra-thin Equipment Dehumidify Module (EDM) equipped with a desiccant wheel to remove moisture from the air in the cleanroom, thereby maintaining a low-humidity environment inside the EFEM. The study also involved a comprehensive performance evaluation of the humidity control range within the EFEM. It investigated the effects of various parameters: changes in relative humidity of the air supplied to the EFEM (40-45% RH at 23°C), changes in velocity at the ULPA filter side (0.2-0.7 m/s), rotation speed of the desiccant wheel (5-20 RPH), regeneration temperature (120-150°C), and regeneration airflow (4-7 CMM) on temperature, humidity, power consumption, and internal humidity changes during the operation of the EFEM. Under the optimal conditions for the EFEM, the lowest average internal humidity achieved was 1.3% RH.
High potent OSD facility: Process containment and clean room design
Emilio Moia – Ilaria Beccio
The production of highly potent products, OEB 4 and OEB5, involves creating an environment in which containment requirements meet cleanliness requirements. In addition, process containment measures, isolators and related components, must be identified taking into account potency, type of drug handled (powder, granulate) and thermos-hygrometric condition. The objective of the article is to present the strategy and solution designed for a high containment facility for oral solids.

PARALLEL SESSION – LIFE SCIENCE 

The Closed Processing Advantage: Optimizing Biopharma Facilities
Sarah Le Merdy
Are you OPEN to CLOSE your bioprocess? Join us as we explore the future of biopharma facility design and operations. Discover the key market trends driving the need for single-use, closed processing solutions, and learn how closed processing can reduce costs, accelerate time to market, optimize facility utilization, and minimize risks.
Learning points:
1. Understand the current market trends driving the need for closed processing in biopharma, including the rise of novel modalities, multi-product manufacturing, and the demand for more flexible facilities.
2. Explore the benefits and value drivers of closed processing, including facility utilization, sustainability, cost reductions, and labor savings.
3. Examine the evolution of biopharma facility design, comparing traditional layouts to innovative, modular, and ballroom-style configurations.
4. Learn about industry efforts to harmonize guidance and best practices, fostering a collaborative environment for closed processing adoption.

How CFD can support Contamination Control Strategy in cleanroom design – case study
Lapo Galligani – Toni Valente
This work explores the application and strengths of numerical simulation techniques, specifically Computational Fluid Dynamics (CFD), in supporting the design of a pharmaceutical cleanroom and its ventilation system. The study focuses on the fill-finish area within the new production department for injectable anesthetic drugs at the Pierrel facility in Capua.
The examined space houses a filling line protected by Restricted Access Barrier Systems (RABS), integrated into a cleanroom of Grade B according to EU Good Manufacturing Practice (GMP) standards, employing “full coverage” air distribution. CFD simulation is employed to analyze and manage airflow within the cleanroom, a challenging task given the substantial air volume involved (approximately 140,000 cm/h) and the need to integrate air intake points with the installation of process equipment. In cleanrooms of this type, the correct implementation of unidirectional airflow plays a crucial role in Contamination Control Strategy, directly impacting the protection of components in direct contact with the product during post-decontamination/sterilization transfer and line setup operations.
CFD emerges as an essential tool not only in aerodynamic design but also in implementing effective operational procedures for product contamination control and prevention. Simulation results are then compared with smoke studies conducted during the qualification phase in the field.

Annex 1: Contamination Control Strategy for Material Transfer in the Aseptic Area: Best Practice for Packaging and Surface Disinfection
Renee Buthe
The European Union EudraLex: Volume 4, Annex 1 speaks to the necessity of having sterilization packaging that is compatible with disinfectants used for material transfer into the aseptic area.
Sterilization packaging is designed to allow for steam penetration and aeration during autoclaving, but is the packaging compatible with disinfectants used for surface decontamination when material transfer is needed? Novel studies have been completed with packaging material to test the compatibility and penetrability with different disinfectants. This information is critical when creating a contamination control strategy for a facility.
Some material transfer methods include:
• Manual disinfection with disinfectants and/or sporicides
• Vaporized Hydrogen Peroxide (VHP) pass through decontamination
• Pass through autoclave sterilization
• Removing the outer layer of wrapping material
Ensuring the material compatibility with different methods is critical to the parts and materials moving within a facility. Mapping this information for each facility is critical to the CCS. These processes should ensure the removal of bioburden while moving the materials into the facility in a reproducible way, ensuring the efficacy on the wrapping materials.
A case study will be presented where a major ATMP CAR-T manufacturer in Europe is using a kitting method for material transfer due to limitations with sterilization capabilities.

How to harness robotics in contamination controlled environments
Andrea Tanzini – Filippo Parini
Although the pharmaceutical industry is characterized by slow adoption of new technologies, recently, the European Medicines Agency (EMA) took the lead in pushing for process improvements using technologies already established in other manufacturing sectors. Foremost among these technologies, robotics is a technological driver, and its implementation in the pharma field should cause a big change. This paper aims at describing the regulation changes mainly in aseptic manufacturing and the use of robotics in the pharmaceutical environment to fulfill GMP (good manufacturing practice). Special attention is therefore paid at first to the regulatory aspect, explaining the reasons behind the current changes, and then to the use of robotics that will characterize the future of manufacturing especially in aseptic environments, moving from a clear overview of robotics to the use of automated systems to design more efficient processes, with reduced risk of contamination. This paper should clarify the regulation and technological scenario and provide pharmaceutical technologists with basic knowledge in robotics and automation enabling the cultural shift of the pharmaceutical industry.

Leveraging emerging technologies for hydrogen peroxide bio-decontamination: from novel process data to real process impact
Martin Novak
Hydrogen peroxide bio-decontamination plays a key role in applied Contamination Control Strategies in pharmaceutical barrier systems. The EU GMP Annex 1 provides increased opportunity to introduce emerging technologies, including advanced chemical and enzyme indicators, hydrogen peroxide sensors and computer fluid dynamics simulations.
How can we transform the potential of novel data into real end-user value? Current strategies of bio-decontamination cycle development and validation with biological indicators are well established and successfully applied. Augmenting those strategies may be challenging; novel data, while interesting, may create more questions than answers. Fundamental understanding of new technologies and their relation to biological indicator data as well as the key kill facilitating process variables is critical for their successful implementation.
This presentation focuses on 3 key objectives
1. Introduce computational fluid dynamics simulations for hydrogen peroxide bio-decontamination and showcase the benefits of data-driven solutions
2. Evaluate the performance of Enzyme Indicator technology and offer data-based discussion about potential use cases
3. Explore the potential for further development in isolator hydrogen peroxide bio-decontamination to achieve meaningful performance improvements 

Potent OSD Global Supply
Marco Annoni
An in-depth knowledge of the process and of the product used, combined with an entire team of engineers, are the fundamental basis in the design and manufacture of integrated processing systems for turn-key plants. In this scenario, also containment is to be approached as a global engineering issue in a manufacturing plant and must be designed on a risk based approach. A preliminary analysis has to be carried out to identify criticalities and potential risks, considering both the pharmaceutical requirements of the process to be performed and the plant conditions in terms of regulations, layout and industrial target. With hundreds of installations for dispensing, handling, granulation, tableting, capsule filling and coating for 3 to 5 OEB products, both for production and R&D applications, IMA Active has a wide and constant knowledge of processing highly potent products. All IMA equipment are already designed according to basic criteria to process high potent products. Starting from an OEB level of 3, additional protective measures are applied on the machine based on the following design concepts:
– Isolation of the processing area
– Minor surface in contact with the product
– Management of air displacement
– Increasing the level of automation
– Protecting point of access
– WIP or CIP to avoid the contact with the product during cleaning operations
During the presentation all go through all these point to discover how to properly design a high containment solid dose plant.

PARALLEL SESSION – ENVIRONMENTAL CONTROL AND MONITORING

Future QC Testing using automation and robotics – automated Environmental Monitoring
Anke Hossfeld
The pharmaceutical industry is embracing Pharma 4.0 and the automated, continuous, and real-time-monitored production processes this entails. Microbial quality control (QC) must adapt accordingly. As customers strive to further improve productivity, data integrity, and reliability in QC testing by reducing time-consuming and error-prone manual activities, we are adapting our leading environmental monitoring technologies, sterility testing, bioburden testing to function in integrated robotics, automation, and digitalization solutions.
Automated processing of samples creates the opportunity, and in many cases the necessity, to save and process data digitally. This is why digitization plays a key role in any QC automation strategy, paving the way for improved data accuracy, integrity, and traceability. All consumables for automated solutions should thus carry bar codes that allow automatic read-in and processing of sample information. Paperwork and isolated spreadsheets are no longer needed, reducing the likelihood of documentation errors and helping to increase sample throughput.
This session will provide an overview of the capabilities of full QC automation in laboratories and clean rooms and discuss the benefits and challenges of automation. A case study on automated viable air monitoring will be presented to demonstrate the advantages in terms of improved data traceability & to overcome resource gaps and the challenges it has in terms of facility design and consumables

Continuous monitoring (Viable and Total Particle) according to the final revision of the Euopean GMP Annex1:2022 “Manifacture of Sterile Medicinal Products”) – new requirements, next challenges and comparison with the previous regulation guideline
Diego Bompadre
Important requirements of the European GMP annex 1:2022 have changed for the qualification of cleanrooms and for the continuous monitoring of viable and total particles in aseptic environments. The purpose of this presentation is mainly to highlight the relevant aspects about the differences between qualification and continuous monitoring as misinterpretations and errors are often still common. Continuous environmental monitoring represents one of the most relevant and effective tools to assess in real time the potential risk of contamination in critical environments and to ensure that the environment for sterile operations is maintained in a qualified state. The purpose of the environmental monitoring program is to:
– Provide assurance that cleanrooms and clean air equipment continue to provide an environment of appropriate air cleanliness, in accordance with design and regulatory requirements.
– Effectively detect excursions from environmental limits triggering investigation and assessment of risk for product quality.

Microbiological environmental monitoring: a comprehensive analysis and procedure analysis for continuous monitoring according to EU GMP ANNEX 1 2022
Miriam Magri, Francesco Romano
The release of new Annex 1 has strengthened the importance of a contamination control strategy within controlled environments. The detection and the continuous monitoring of microbial, pyrogen & particles is becoming a key factor. The awareness and the knowledge of sampling techniques and equipment used becomes therefore fundamental for the correct operation and results interpretation. The proposed paper deals with the evaluation, design and validation of microbial environmental sampling process. Study consisted in two main activities. An experimental evaluation to quantitative evaluate and assess the vitality of sampling methods investigating various agar media nutrient quality and quantity, test strains, sampling time and environmental conditions. Data inherent the agar media recovery efficiency obtained have subsequently used for sampling methods and instrumentation experimental tests. In this case, experimental campaigns have been conducted for the comparison and the validation of different microbiological air sampler performances in clean and CNC environments. Scripted test procedures have been implemented to assure repetitive conditions both for personnel behavior and sampling instruments operations. Results show how a correct choice of the quality and quantity of agar media coupled with the right air sampling technique may guarantee a safe and reliable microbial environmental monitoring even for relative long sampling time and off-design thermo-hygrometric conditions.

Development of an environmental monitoring program for a cleanroom in the life science industry
Lene Blicher Olesen
Evolving an environmental monitoring program for cleanroom in the life science industry, that needs to be compliant to EU GMP Annex 1, involves several activities to ensure the environmental monitoring program will be robust to monitor contaminants that potentially can affect the final product.
The presentation will, with background in a case story from the industry, describe the sequence of activities that need to be performed and implemented before finally setting up the environmental monitoring program

Basic and beyond. How to prepare proper contamination control strategy document
Hasim Solmaz
One of the most important news in pharmaceutical industry for regulatory standpoint was New GMP Annex 1 revision in 2022. More than a revision, 99 new pharagraphs and several new definitions, new GMP Annex 1 become a completely new document for most of us. Contamination Control Strategy (CCS) is one of those new requirements. According to the GMP Annex1 2022; «A Contamination Control Strategy (CCS) should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organizational) and monitoring». Since this is a quite new concept, this paper will summarize it with 3 easy and “self-explanatory” steps to make it easy to remember and implement

Are all viable microorganisms culturable?
Michel Thibaudon
No, not all viable microorganisms are culturable using traditional laboratory methods. Despite this, all standards and regulations dealing with environmental biocontamination use cultivation methods as an exact representation of the presence of microorganisms in the air or on surfaces. Only European standard EN 17141 highlighted the notions of “viable” and “cultivable” and contains an informative annex on alternative methods in environmental microbiology for detecting viable microorganisms. The tables of values clearly indicate the notion of ‘cultivable’. Unfortunately, the latest version of GMP Annex 1 has not considered the comments made on this important point and continues to indicate the notion of viable for colonies obtained by culture. Although many microorganisms can be cultured in the laboratory, there is still a significant portion of microbial diversity that remains uncultivated. The percentage of culturable environmental moulds can vary depending on several factors, including the conditions of the culture medium. It is important to note that many moulds can exist in the environment in a non-culturable or viable but non-culturable (VBNC) state. The VBNC state refers to a physiological state in which certain microorganisms are alive but cannot be cultured using standard laboratory methods. However, VBNC microorganisms can retain their virulence and pose a potential risk to human health

PARALLEL SESSION – HEALTHCARE

Evaluation of source strength in a dispersal chamber of three new generation Clean Air Suits
Berit Reinmüller
The number of airborne bacteria-carrying particles in the operating room is considered an indicator of the risk of infections to the patients undergoing surgery susceptible to infections. Today the supply air in the operating room is HEPA-filtered, the main source of airborne microorganisms is people. The filtration efficacy of the fabric in surgical clothing systems affects the number of particles emitted from people to the air. Clothing systems for cleanrooms and associated controlled environments such as ultraclean air operating rooms are mainly tested with regard to material properties, such as particle generation, particle filtration, and resistance to wear, and comfort. Dispersal chamber or “body-box” has been used for studying the protective efficacy of clothing systems in use. A modified dispersal chamber is installed at Chalmers University of Technology in Göteborg. Tests have been performed on three new generation Clean Air Suits, all reusable, and consisting of blouse, trousers and hood.
Results show that all three systems fulfill the requirements of source strength in SIS-TS39:2015, and the dry penetration test of clean air suits high performance in EN 13795-2: 2019. The influence of the new generation Clean Air Suits in ultraclean air operation rooms will be discussed

The development of ultraclean air operating rooms
Bengt Ljungqvist
In UK during the 1950s, airborne microorganisms was measured in operating rooms and often showed large quantities of bacteria.
Sir John Charnley succeeded in reducing the rate of infections for total hip joint. Charnley demonstrated a correlation between microbial air contaminants and infection rate. His result were confirmed through a prospective controlled multicenter study. In the 1970s and 1980s ultraclean air operating rooms, were used for surgery susceptible to infections, mainly orthopedic surgery. The air movements were parallel through the inner zone with air velocities up to 0.5m/s. This often gave air change rates 5-10 times higher than the air flows used for conventional operating rooms with turbulent mixing air. Since the 1970s, air supplied to ultraclean operating rooms has been filtered through HEPA-filters. Since 1990s most air supply systems with unidirectional air flow are installed without sidewalls or partial walls. Today, many air supply systems providing UDF, have air velocities below 0.3m/s. During ongoing surgery, this results in a disordered airflow pattern above the operating table resembling that of total mixing air. The dilution principle becomes valid. The chosen clothing systems play a determining role. This gives that the number of people present in the operating room impact the concentration of CFUs. When designing the necessary air volume flow in operating rooms the number of people and their clothing system should be taken into consideration

Operating theatres are not all the same: can laminar air flow really make a difference? A correlation study between HVAC systems and surgical site infections
Agnese Lucesoli
Air quality in operating theaters (OTs) is a key factor in preventing surgical site infections (SSIs). To this end, HVAC systems should ensure the highest air quality, abating microbial contamination on the surgical field. This is especially important for high-risk procedures such as transplants or prosthetic implants. Recently, the effectiveness of laminar airflow (LAF) ventilation systems in preventing SSIs has been much debated.
This work provides a correlation analysis between OT HVAC systems and SSIs, based on data from 14 hospitals in the Marche Region in 2018 and 2019.
Technical data were taken from the validation tests periodically carried out in each OT. We considered as LAF only HVAC systems with a unidirectional air flow reaching at least an ISO 5 class on the operating field according to ISO 14644-1. These data were then correlated with the number of SSIs occurred in patients undergoing surgery for a total of 899 surgical procedures. We observed N=38 SSIs for a prevalence of 4,2% (95% C.I. 3,0-5,8). Procedures performed under a non-LAF system were N=561 (62,4%; 95% C.I. 57,3-67,8), N=338 (37,6%, 95% C.I. 33,7-41,8) under a LAF system. Of the 38 infections, N=29 occurred under non-LAF systems for a respective prevalence of 5,17% (C.I. 3,5-7,4), while N=9 in a LAF environment for a respective prevalence of 2,66% (C.I. 1,2-5,0). We performed a logistic regression that showed a low likelihood of surgical infection in presence of a LAF system (OR=0,69; C.I. 0,3-1,7).