FAQ cleanroom

Working in a clean room is subject to strict specifications with regard to interior design, clothing, rules of conduct, etc. In general, it is important to prevent particles, germs, etc. from contaminating the corresponding medicines, devices and other products. This means that special abrasion-resistant clothing must be worn in a clean room, which prevents dander, hair, bacteria and dust from being carried into and distributed in the clean room. These are complete suits with a mask or a combination of pants, outerwear, mouth and nose protection, hair protection and gloves or similar.

The workplace in a clean room requires numerous rules of conduct for employees. Slow movements are required to keep the emission of particles low. In addition, the production lines in a clean room are much smaller. All processes must be clearly separated from each other and there must be no cross-contamination through the air. An example from the pharmaceutical industry: In a clean room, aspirin is pressed in one machine and morphine tablets in the other. Both production lines must remain completely separate from each other, the air flows must not mix, so that no morphine ends up in the aspirin. In addition to structural conditions, integrated extraction systems ensure that no cross-contamination occurs. In addition, dirt must be removed immediately and safely. Here, for example, our specially manufactured vacuum cleaners for (flammable) liquids and dust are used.

Harmful substances such as chemicals, acids and alkalis as well as pharmaceuticals are processed in numerous clean rooms. To ensure that employees are protected as best as possible from the harmful properties of the substances, numerous safety measures must be observed. This includes, among other things, extraction with industrial vacuum cleaners - integrated as an extraction system in the production line - or in a mobile version, for example for immediate cleaning of the workplace or in the event of accidents. The basic prerequisite for this is that the design of the clean room vacuum cleaner, including all accessories, is tailored to the individual application. In order to select the right industrial vacuum cleaner with the appropriate filter elements and accessories for the respective clean room in order to prevent health hazards, various factors must be taken into account: Which hazardous substances should be vacuumed? What form do they have (liquid/solid)? Which type of clean room vacuum cleaner and which filters are required for the medium? How must/can cleaning and disposal be implemented and what must be taken into account? On the basis of these questions and beyond, the right industrial vacuum cleaner with the appropriate filter elements for the respective application in the vacuum cleaner is selected. This significantly reduces the risk of contamination and thus health hazards.

Safety is the top priority in every clean room. Clean rooms are demanding environments in which the protection of employees, the manufactured products and the environment are paramount. Human behavior and the clean room vacuum cleaner used, including accessories, must be tailored to the respective application in order to ensure the highest possible level of safety. It is therefore important for each clean room, based on the respective application, to choose the right clean room vacuum cleaner with the right accessories including the right filters.

Dangers arise particularly during coupling and decoupling processes that remain invisible to the user in daily use: Dust is deposited inside the accessory and the medium could escape when the accessory is changed. For our customers, we test different types of accessories with a special hygroscopic neon fine dust (particle size > 0.6 μ) under black light. Hidden contamination on the components can be detected in a video analysis with the appropriate magnification.

Technical cleanliness is a clearly defined degree of unavoidable particle contamination, which is the maximum that may be present - for example on the surface of a component. The so-called residual dirt must be so small that there are no restrictions or damage within the system after an individually determined size. If this is guaranteed, a system is considered technically clean. Technical cleanliness is usually associated with the manufacture of components for the automotive industry in accordance with VDA 19, but also plays an important role in semiconductor production or micromechanical assembly, medical technology or e-mobility. Products that are sensitive to cleanliness in terms of technical cleanliness can be manufactured, processed or packaged etc. in a clean room according to DIN ISO 14644-1 as part of what is known as clean production. As the highest cleanliness area, a clean room has the best prerequisites for complete freedom from contamination. On the one hand, the formation of particles is avoided through protective clothing, behavior and structural equipment. On the other hand, our clean room vacuum cleaners ensure reliable particle cleaning, whether within the production line or during manual cleaning of the workplace, etc. If there are risks for the environment, any residual products that cannot be saved must be burned in special disposable systems.

In the manufacture of pharmaceuticals, sterile products, etc., strict contamination control is important to ensure that only safe products are placed on the market. In the medical/pharmaceutical sector in particular, clearly defined behaviors as well as control and monitoring functions are necessary across the entire process chain in order to protect the health of consumers. Processes and associated behavior are defined in various guidelines. In 1987 the document "Guideline on General Principles of Process Validation" was issued by the US Food and Drug Administration (FDA), which defined two areas: "critical" areas where sterile products, containers and closures are exposed to the environment, and the "Monitoring" area, in which unsterilized products, materials to be processed and containers/closures are to be prepared.

The guidelines for quality assurance in production, equipment, media and clean room environment in the production of medicinal products and active ingredients are summarized under the term "Good Manufacturing Practice" (GMP). The EU GMP guidelines are set out in the EU GMP Guide. Annex 1 of the "Good Manufacturing Practice" guidelines is considered the most important European regulation for the manufacture of sterile medicinal products. The regulations are constantly being revised and adapted to modern demands or changing requirements - most recently in 2020. The aim of the guidelines is to prevent cross-contamination, for example through special clothing and air and lock systems - and thus to ensure the sterility of the manufactured products guarantee. Chapter 3 states: “Premises and equipment must be so arranged, planned, constructed, retrofitted and maintained that they are suitable for the intended operations. Their arrangement and design must be aimed at minimizing the risk of defects and allowing for thorough cleaning and maintenance in order to avoid cross-contamination, accumulation of dust or dirt and, more generally, any effect detrimental to the quality of the product." At the same time, it applies To implement a contamination control strategy, i.e. to continuously monitor and review the contamination risks and implemented contamination prevention measures to ensure that the end product is contaminated by cellular and microbial residues as well as particulate matter.

For clean rooms in the pharmaceutical/medical device sectors, the clean room classes according to the EU GMP guidelines apply. Annex 1 defines the limit values for the maximum permitted number of particles per square meter in the room. These are divided into classes A, B, C and D - from A as the purest level to D with the highest maximum permissible particle concentration. Which clean room class must be used for the respective medical product depends on the exact industry and the conditions in which it is produced.

KRAHNEN offers the right suction solution for the different cleanliness classes with high-performance HEPA/ULPA filters and other filter solutions.

In clean rooms, particularly high cleanliness and safety requirements apply. When vacuuming in a cleanroom, it is important to prevent or minimize particulate contamination in or via the air. In addition, the vacuum cleaner itself must not be a source of dust or other contamination. At the same time, in potentially explosive working environments, there is a risk that a conventional vacuum cleaner will ignite explosive material. Special ATEX-protected cleanroom vacuum cleaners from KRAHNEN meet the demands placed on a vacuum cleaner in cleanliness-sensitive and potentially dangerous working environments. Due to their structural design, they are easy to clean; the majority of clean room vacuum cleaners can also be autoclaved for GMP applications.

In addition, the integrated filter system is very important for a clean room vacuum cleaner, since the suction material in the vacuum cleaner is mainly separated by appropriate filters. The cleanroom vacuum cleaner should have several filters both for picking up normal suction material and for zone separation with combustible substances. A risk of escaping should be avoided with regard to the grain size of the particle and a possible filter breakage. Particular care should be taken when picking up hazardous substances. In order to avoid the risk of contamination, the appropriate filter element must be present in the suction cup for the respective application. It is therefore important to inquire about the following aspects before selecting cleanroom vacuum cleaners and filter elements: design, purpose, handling, cleaning and disposal.

KRAHNEN offers you the manufacturer's proof of the quality, fineness, class, as well as the tightness test of the filter elements after installation in the clean room vacuum cleaner, so that you are guaranteed to be able to vacuum safely.

While Part I of the EU GMP Guide is aimed at manufacturers of medicinal products, Part II is aimed at manufacturers of active ingredients. The "Good Manufacturing Practice for Active Substances" contains information on guidelines for quality management, e.g. B. for placing active ingredients and intermediates on the market, the required water quality in the manufacture of active ingredients, in-process controls, batch mixing, the creation of contamination profiles, repeat tests and much more.

The principles and guidelines formulated by the European Commission for the manufacture and manufacturing environment of medicinal products and active ingredients specify "Good Manufacturing Practice" (GMP for short). The guidelines, first published in 1989, contain requirements for quality assurance with regard to production, equipment, media and the clean room environment. The aim of these regulations is the possibility of a process review. The EU GMP Guide contains detailed guidelines for the interpretation of these formulated European GMP principles and guidelines. The most important European regulation of the regulation is Annex 1, which is constantly updated and adapted to modern requirements.

Classes for the manufacture of sterile medical products according to EU-GMP

Annex 1 "Manufacture of sterile medicinal products" is the first appendix of the EU GMP guidelines on "Good Manufacturing Practice" and is the most important European guideline for the manufacture of sterile medicinal products. It contains guidelines that serve to keep the risk of contamination with microorganisms, particles and pyrogens as low as possible. Annex 1 defines the various clean room classes based on microbiological contamination and maximum particle values in the air. The classes are divided into levels A to D, with A being the purest level with the lowest maximum permissible concentration of particles. Clean room classes must not be skipped. In order to operate clean room class A, all classes from D to A must be run through. In addition, Annex 1 gives clear specifications for air quality, sterilization, behavior of staff, requirements for the design of premises, minimum intervals for repeated qualification of the premises, quality controls and much more.

Annex 1 was first published in 1971. Since then, it has been continuously revised and modernized, for example as there are new technologies for the manufacture of sterile medicinal products or modern principles such as quality risk management. The last major change was in 2020 - a major innovation here was a concept for contamination control (Contamination Control Strategy) throughout the manufacturing process, including all associated areas. This includes measures to reduce contamination risks and the monitoring of these same measures. The aim is to prevent the respective end products from being contaminated by the smallest particles.

The EU GMP guidelines, Annex 1, specify rougher classifications for cleanrooms than DIN ISO 14644. These rougher classifications are usually sufficient for suppliers, manufacturers and operators of cleanrooms.

DIN EN ISO 14644 is an internationally valid standard for clean rooms and associated areas. DIN EN ISO 14644 defines the degree of purity of the air in terms of particle purity. The particle concentration per m ³ is specified. Air purity is divided into nine different ISO classes; ISO class 1 is the purest class. Clean rooms are divided into clean room classes according to the measured values of these ISO classes. In addition to particle limit values, DIN EN ISO 14644 also specifies test methods to determine cleanliness classes.

Sensitive products can then be manufactured in the corresponding clean rooms of a specific clean room class. DIN EN ISO 14644 is important for the semiconductor, aerospace, optical and pharmaceutical industries. In addition, food manufacturers as well as medical technology and healthcare also use DIN EN ISO 14644 as a guide. The pharmaceutical, food, medical technology and healthcare sectors also use the applicable EU GMP guidelines.

In contrast to the clean room classes according to the EU GMP guidelines, Annex 1, the more modern DIN EN ISO 14644 at the upper end allows much finer distinctions for even greater cleanliness.

According to the DIN EN ISO 14644 standard, nine cleanliness classes are distinguished. The degrees of cleanliness are defined according to the maximum permissible particle concentration per m ³ of air. Cleanliness class 1 is the cleanest class, allowing the fewest particles in the air.

Clean room classes according to ISO-14644-1

The beginnings of the first clean room standards began in the 19th century with the first hygiene regulations for doctors during operations. This resulted in an awareness of contamination in all other areas and the clean room technology was developed. However, it was not until the 1960s that modern clean room technology was advanced by the development of a clean room concept with low-turbulence air flow. On this basis, the first standardization for the requirements of clean room technology was finally created in 1963 with the United States Federal Standard 209 (FS 209). The US Federal Standard 209E was the standard for clean room classifications until the 1990s and was updated five times until 1992.

The US standard was replaced by DIN EN ISO 14644 in November 2001. All standards and guidelines from all countries and industries have been summarized in this standard so that there is a guideline that is constantly being optimized and adapted to modern requirements.

In addition, specific guidelines have been developed in various industries and areas of work.

The VDI 2083 guideline, which describes the current state of the art, has been published by the Association of German Engineers for several decades. The guidelines are based on ISO 14644 and detail their guidelines. VDI 2083 is a national standard that deals with industry-specific aspects and topics such as energy and cost efficiency. ISO 14644 and VDI 2083 are now considered equivalent standards for clean room technology. The VDI Guideline 2083 is used, among other things, in the food industry, microelectronics and the pharmaceutical industry and research.

In the pharmaceutical industry, the first GMP rules (Good Manufacturing Practice) for the manufacture of medicinal products were published in 1962, initially without legal obligation. In 1978, the FDA published the first legally anchored GMP guidelines: the manufacturing process of pharmaceutical companies could now be monitored. For Europe, the guide was adapted in 1989 as an EU GMP guide with clean room classes A, B, C and D. Annex 1 of the guide defines the limit values for the microbiological contamination of the room air. The standard is also used in the food and cosmetics industry, biotechnology, medical technology, etc., among other things.

The main drivers of the further development of modern clean room technology are the pharmaceutical and semiconductor industries.

Over the years and decades, machines and processes have become more sophisticated and modern - accordingly, there used to be other classifications. Even the first classifications included classes that could not be achieved according to the standards of the time. As later classifications show, the level of cleanliness has long since been exceeded: cleanroom class A of the EU GMP guidelines corresponds to ISO class 5 and already meets particularly high cleanliness requirements.

In general, clean rooms are characterized by a low concentration of airborne particles and germs. They are used where sensitive products are manufactured that must not be damaged, contaminated or destroyed by the corresponding particles. These include, for example, the pharmaceutical and food industry, the semiconductor and chip industry, etc. Each industry, each company and each product has different requirements that the respective clean room must meet. This affects, among other things, the design of the room, the existing clean room technology, the frequency of filter changes, the behavior of the employees and much more. The exact requirements that the respective clean room must meet can be found in the industry-specific regulations. Depending on the industry, product or similar. the clearly defined clean room classes of DIN EN ISO 14644, the EU GMP guideline, the VDI 2083 guideline apply, which result in clear requirements for premises, systems, machines, protective clothing and the behavior of the employees.

According to current regulations, a clean room is a room in which the concentration of airborne particles is very low and this can also be controlled and the clean room can be classified accordingly. In addition, the space must be designed, constructed and operated in such a way that the supply, generation and retention of airborne particles within the space can be controlled. A room is therefore a clean room if it meets the minimum requirements that are placed on a clean room in accordance with DIN EN ISO 14644, the EU GMP guidelines or the VDI 2083 guideline.

A clean room is a manufacturing facility that is very similar to a clean room; the basic structure is very similar. However, the tolerances on particle content and particle sizes are much less stringent and more generous in comparison. In clean rooms, particle sizes of up to 600 micrometers are tolerated on components. For comparison: In the clean room, a significantly lower limit applies (down to 5 microns). The material properties of the particles are much more important than just the particle size: Mechanical components, for example, are more likely to be destroyed by a few hard particles than by a larger number of softer ones. Accordingly, the ventilation and filter technology used can be dimensioned smaller. As a result, the acquisition and operating costs also differ significantly. Clean rooms are defined according to the technical cleanliness of the VDA 19 (international ISO 16232) and are mainly used in industry and production. Clean rooms are standard in the automotive industry, mechanical engineering, plastics technology and electrical engineering, among other things - i.e. wherever it is necessary to prevent small dirt particles from contaminating and damaging parts, components, etc.

Clean room buildings are complete buildings that are operated exclusively under clean room conditions. From special walls, ceilings, doors and glazing to ventilation technology that flows through the entire building to the silicone used for the joints, the entire building is designed as a clean room. This also includes individual requirements such as the separation of personnel and material flows. Some clean room buildings are also decoupled from vibration technology.

The need for a specific clean room class results, among other things, from the industry and the manufactured products. DIN EN ISO 14644, the EU GMP guidelines or the VDI 2083 guideline provide corresponding information and specifications for this. A clean room is very expensive to plan and implement and later especially to operate - the higher the clean room class, the more expensive it is, since the demands on the technology used, cleaning intervals, protective clothing for employees, etc. are increasing. In order to avoid a cost explosion, it is worthwhile to plan the clean room exactly according to the needs and requirements and not to oversize it by choosing a much higher clean room class or by planning the clean room too large. The VDI Guideline 2083, which also provides information on energy and cost efficiency in clean rooms with reference to DIN EN ISO 14644, provides support during planning. Thanks to the measuring options available today, modern technologies, experience with regard to risks, etc., it is possible to design and implement a clean room exactly according to requirements. It is also worth taking a look at the work areas adjacent to the clean room. It makes sense to design these as clean rooms/clean areas, for example to shorten the way to the clean room (due to decontamination regulations) and thus also save costs.

According to the "Guideline on General Principles of Process Validation" issued by the US Food and Drug Administration (FDA) in 1987, the environmental guidelines for "critical" areas where sterile products, containers and closures are exposed to the environment, such as is defined as follows: “Air in the vicinity of exposed sterile containers/closures and filling/closure processes is of acceptable aerosol quality if the particle count per cubic foot is less than 100 (when sized up to 0.5 μm or larger) in the workplace and during filling /closing airflow is measured at a distance of no more than a foot. The agency (FDA) recognizes that some powder filling processes generate high concentrations of suspended solids, which by their nature do not pose a risk of product contamination. In these cases, however, it is important to obtain air measurements that reflect the level of external contamination to which the product is exposed.

Air in critical areas should have a HEPA-filtered laminar flow at the point of use and at a sufficient velocity to steer suspended particles away from the point of use. Usually 90 ft/m (0.5 m/s) +/- 20% is sufficient as speed; however, if processes cause high levels of suspended solids or plant design disrupts laminar flow, higher velocities are required. In addition, the air should also be of high microbiological quality; A maximum of one colony-forming unit per 0.3 m ³ is permissible.

Critical areas must also be pressurized to adjacent less clean areas (min. 2.5 kPa); a pressure differential of 0.05 inches of water is acceptable.”

According to the "Guideline on General Principles of Process Validation" issued by the US Food and Drug Administration (FDA) in 1987, the environmental guidelines for "controlled" areas (monitoring) in which unsterilized product, process materials, and containers/ Closures are prepared as defined as follows: “Air is generally of acceptable quality when the particulate matter per cubic foot (class 100,000) of indoor air does not exceed 100,000 particles (within a size range of 0.5 μm or greater) when measured near exposed materials in the facility. Microbiologically, up to 25 units per 0.3 cubic meter can be measured. In order to maintain air quality in a controlled area, adequate airflow and positive pressure must be achieved for adjacent (uncontrolled) areas. An air volume corresponding to at least 20 air changes per hour and a differential pressure of 2.5 kPa (door closed) are permissible. When the door is open, the outward airflow must be sufficient to prevent contaminants from entering.”

In a clean room, the air is filtered to keep the dirt particle load from dust, germs and aerosol particles as low as possible - both inside the clean room, so that the manufactured products are not soiled, and in the exhaust air area, for example when it comes to Substances that are hazardous to humans and the environment. A filter used in a clean room must therefore meet high demands and be able to separate the smallest particles, but also germs and particles in the submicron range. The precise requirements for air filtration and thus the filter elements are essentially derived from ISO 14644 and the EU GMP guidelines. Coarse and fine dust filters as well as high-performance particulate filters (HEPA/ULPA) for the smallest particles are used in the clean room.

The same criteria also apply to clean room cleaning, where filtering must also be guaranteed. The KRAHNEN clean room cleaners are available for various ISO classes and OEB/OEL values and are equipped with HEPA/ULPA filters and other filter solutions.

Particulate matter filters such as EPA, HEPA and ULPA filters are subject to the provisions of EN 60335, among others. In order to be able to assign the respective filter to a specific filter class, the degree of separation must be determined. This results in the separation performance and the efficiency of the HEPA filter. The higher the degree of separation, the better the filter performance. The filter separation efficiency usually results from the mean value of random measurements using particle counting methods. A liquid or solid test aerosol is used here. The degree of separation is then determined for the particle size that the filter is most difficult to separate. This particle size is called MPPS (Most Penetrating Particle Size) and is individual for each filter. The amount of particles entering the system via the filter is measured and set in relation to the amount/concentration of substances entering the filter.

Air filtration in a clean room is guaranteed, among other things, by a sophisticated filter system. Coarse and fine filters are used for pre-filtration of the outside air. In addition, HEPA and ULPA filters separate the smallest particles such as germs and ensure a very high level of air purity. The HEPA filters are integrated in the ceiling diffuser or as a terminal filter in the filter ceiling. The corresponding filters lose their performance after a certain period of operation, which is why regular filter changes are necessary. This is the only way to ensure that the respective clean room class is free of particles. When changing the filter, it is also important to carry it out without contamination.

KRAHNEN provides additional support for air purity with the Safety Change vacuum cleaners, with which combustible and harmful dust can be vacuumed without contamination and disposed of accordingly. The vacuum cleaners contain downstream Safety Change HEPA filters H14 for clean room class ISO 4/5 or EU-GMP A.

There are limit values for cleanliness in clean rooms that must be complied with. Since processes take place in a clean room, be it laboratory operations, the manufacture of components or the manufacture of medicines, etc., involving personnel and machines, a certain degree of contamination automatically occurs. Particularly noteworthy here are contamination from particles such as dust, germs or the like, but also, for example, contamination of production machines from oils or grease. For this reason, clean rooms must be cleaned according to various standards and regulations in order to ensure the safety of personnel and products at all times. DIN EN ISO 14644, the EU GMP directive, VDI 2083 and industry-specific standards and specifications apply here. In order to maintain control over the particles – in the pharmaceutical sector also of a microbial nature in particular – the areas must be continuously cleaned during operation using defined cleaning techniques as well as suitable cleaning agents and disinfectants. The clean room cleaning must also be carried out by trained personnel and with a special clothing concept.

While conventional vacuum cleaners are not suitable for use in clean rooms, our special KRAHNEN clean room vacuum cleaners are specially designed for this application and are also suitable for work environments where there is a risk of explosion. The industrial vacuum cleaners are equipped with HEPA/ULPA filters and other filter solutions and are usually autoclavable in accordance with EU GMP requirements.

There are a few things to consider when carrying out clean room cleaning. The guidelines DIN ISO 14644, VDI 2083 and EU-GMP are fundamental for this. First of all, it depends on whether the clean room has to be cleaned with regard to particles or also with regard to microbial contamination. Accordingly, certain cleaning techniques as well as the use of suitable cleaning and disinfecting agents and devices such as special clean room vacuum cleaners are necessary.

Detergents and disinfectants have different effectiveness. For example, in order to comply with the EU GMP directive in the pharmaceutical sector, pharmaceutical manufacturers should choose cleaning agents and disinfectants with different spectrums of activity. It is also important to consider the order in which the cleaning agents are used and their compatibility. In addition to the cleaning agents, the cleaning methods are also crucial in order to keep the clean room clean. This includes, for example, the clearly defined wiping of floors or the use of vacuum cleaners suitable for clean rooms to vacuum up dangerous and flammable dust or liquids.

Industrial vacuum cleaners from KRAHNEN that are suitable for clean rooms are, for example, the Safety Change vacuum cleaners, which allow contamination-free vacuuming and disposal of the vacuumed material. At the same time, the contamination-free change of accessories is possible: You can connect and disconnect suitable accessories without contamination, without the suction material escaping from the openings and contaminating the room or a clean area. Another low-contamination suction solution is available with our endless pack industrial vacuum cleaners.

Blow-fill-seal (BFS) manufacturing technology is now a popular way to manufacture pharmaceuticals in an aseptic manufacturing process. In an optimized system, a mold is first extruded from glass or plastic material (blow), the drug is filled directly (fill) and the container is immediately sealed (seal). Medication dosing is more accurate using BFS technology, and the risk of contamination from staff is lower, since the process is automated in a container. Isolators specially modified for the BFS production technology increase the degree of sterile production environment and ensure the particle and germ-free environmental conditions according to EU-GMP. Isolators are closed systems: Inside the isolator there is a controlled production environment with laminar air flow to minimize the chance of contamination during production.

Since isolators are self-contained systems with their own defined clean room class, it is possible to use them in unclean areas while still ensuring a high level of occupational safety. In individual cases, they therefore represent an alternative to complete clean rooms in the required clean room class.