TRADELABOR has more than 20 years of experience in the control and treatment of air, working with an experienced and qualified technical staff and with the most advanced technology in this area, which together guarantee the quality of the services provided.
The environmental control of classified areas within clean rooms is ensured by systems of humidity control, air temperature, renewal and filtration of the air, by the maintenance of differential pressure and by some good practices such as the cleaning and disinfection of rooms, access restrictions and the implementation of appropriate flows.
When one of these systems or practices fails, it is then a “major event” that can potentially impact the status of the Controlled Atmosphere Zones (CAZs).
The response to these failures indicates how the systems in place are robust enough to correct these events and are frequently a topic of interest for regulatory agencies as they indicate how these systems or how management reacts in case of failure. Understanding where these events may occur and implement a preventive plan and corrective actions allow as much as possible, to minimize the impact of these events on the environment, processes and production programs.
It is important that those responsible for environmental quality understand how these CAA are kept under control. Air Handling Units (AHU) are the main element for controlling the environmental quality of cleanrooms and are one of the elements of air handling systems (HVAC) for controlling dust levels, temperature and humidity and the air flows necessary for air change, recycled and/or new, in cleanrooms. Air handling units force air through High Eefficiency for Particules of theAir (HEPA) to control the level of viable and unsustainable particles in clean rooms. HEPA-filtered air must arrive at a rate sufficient to sweep the particles out of the areas where aseptic activities are performed as well as to maintain unidirectional flow in the critical areas during these operations.
When the cleanrooms are operational, the air handling units can occasionally stop working because of a mechanical breakdown, a power cut, or may be stopped intentionally for preventive maintenance, metrological monitoring or construction work. When these stoppages happen, procedures must be in place to bring these clean rooms back under control. The most probable events, apart from planned stoppages for maintenance or qualification, are power cuts, pressure reversals or excessive humidity. The most probable causes are summarized in Table 1.
Power cuts can have an impact on the correct functioning of air handling units. Variations in pressure are principally caused by human error or mechanical failure. Conditions of excessive humidity are typically due to mechanical, procedural or human error.
Many sites have procedures describing daily operations, but do not have procedures describing actions to be taken if a catastrophe or rare event occurs. The restarting of activities after such events must be defined in the installations disinfection procedure in order to provide a routine response to events which are not routine. It is also invaluable to provide for procedures describing the instructions to be followed when these events arise outside of production periods. The procedures should define the most probable causes of drift and acceptance criteria around those events so that when one of them happens, alternative answers and thoughts already verified previously available.
When CTA stop, or that the environment clean room is disturbed for any reason whatsoever, the resumption of activities may justify enhanced disinfection, restricted access and enhanced environmental monitoring, resulting in a waste of time production and increased costs. A judgment of CTA may only last a few minutes but then justifies the time to restart, the time to perform maintenance work, time to disinfect the affected areas and time to achieve enhanced environmental monitoring.
The overall recovery time for a scheduled shutdown can reach a maximum of a dozen hours per stop and this delay can be even longer for unplanned stops. (1)
When the environment is disturbed, for whatever reasons, immediate actions should include:
• If the procedure involves product exposure, suspend operations as soon as possible. All products undergoing processing must be assessed by the Quality Department, a formal risk analysis or an investigation must be carried out to determine the impact on the procedure or products and to specify the final conclusion regarding the future of the products.
• Isolating the area affected and posting a notice saying that it is not usable.
• Information of the personnel involved: management, quality assurance, microbiological quality control, disinfection support service, technical services …
• Limit staff working in the area. If access is needed then change the over-breeches when leaving the area to avoid contaminating adjacent areas.
• Cleaning or covering equipment and materials when they are transported outside the CAA.
• Cleaning the area affected by the event firstly by removing macro waste or the spillages on the floor with a vacuum with a HEPA filter or with whatever means are appropriate such as wipes, sponges or a squeegee, if applicable.
• Conduct three consecutive disinfections of ZAC.
• Environmental monitoring of both viable and non-viable particles.
• Restarting production in the area.
Is an intervention always necessary?
Not always. Air handling unit stoppages and pressure differential deviations must have procedures in place to avoid unnecessary investigations when these events happen. A short power cut can only justify a limited action such as a single disinfection procedure before authorizing return to production operations. The sites must determine how long the doors can remain open before pressure levels will be too impacted. The sites must also specify how long a pressure deviation outside the established range can be tolerated, how long an air handling unit stoppage is acceptable without justifying a product impact analysis, and scheduling extensive disinfection and enhanced environmental monitoring. The decision to resume production activities without taking specific action must incorporate conditions such as the absence of traffic in the area (or defining what is acceptable in terms of numbers of people or movement), if the doors must remain closed, no presence of exposed products and the maximum duration of pressure deviation or air handling unit stoppage or the duration of air change before resumption of production activities. Most sites must be able to allow an air handling unit stoppage of one to two hours without needing to clean, disinfect or to conduct enhanced environmental monitoring provided that no one is in the area during the event and the environment is not compromised for example by doors remaining open. This absence of action must be supported by an environmental assessment.
When starting a new clean room, it must be qualified according to the ISO 14644-2 standard, Cleanrooms and associated control environments, Part 2; ISO 14644-1, which specifies expectations in terms of periodic monitoring of clean rooms. Most periodic qualifications must be held every 12 months. (2) Counting of nonviable particles in the air for classification and other clean room qualification tests must be done every six months in ISO 5 class areas or more stringent.
The classification is performed once the integrity and effectiveness of the HEPA filters verified. Sometimes, some “clean” jobs are still in progress, which means that no invasive work is done such as cuts, debris on the surfaces … If the remaining jobs generate particles then the classification of ZACs must be lifted .
Damage to the filters or their gaskets during installation or during commissioning an installation represents a risk. To avoid delays, it is best to plan for the purchase of additional HEPA filters just in case. Most companies that carry out CAA classification offer training prior to the installation of HEPA filters to explain to the technicians in charge of the operation how to reduce the risk of damaging filters or their gaskets. Once the HEPA filters are in place, it is suggested that air returns in cleanrooms should be protected by installing an additional filter above. This avoids the dust, paper or debris from work from being sucked into the system. These filters can simply be glued in place.
It is recommended to proceed with the classification when the personnel in charge of the work is always on site to correct any anomaly detected during the classification. At this stage, the clean rooms do not have to be 100% operational with ZAC uniforms, regular disinfections and the start of environmental monitoring. However, the procedures describing flow, dressing, environmental monitoring must be prepared and clothing that protects a minimum must be worn at this stage. It is acceptable during these phases that the outfits are less protective / protective than those worn for future activities, but once the air handling system is operational, the environmental monitoring program must begin. Extensive “triple disinfection” can be performed, however, and unless the cleaning and disinfection program is continued thereafter, this is not necessary. Once the installation is operational, more intensive cleaning or the implementation of exceptional cleaning procedures is recommended to bring the ZAC to its functional level.
Regulatory agencies expect sites to have this type of cleaning integrated into their cleaning and disinfection program as stated in PDA Technical Report 70, which states that “sites are strongly encouraged to have special cleaning and disinfection programs after “shutdown” or after significant work has been completed. (3) A triple cleaning in this case consists in disinfecting a first time, then a second time with a new disinfectant preparation in new buckets and equipment, then a third disinfection with a sporicide.
A “9X” cleaning may also consist of carrying out a triple disinfection every day for three consecutive days. There are many interpretations of triple disinfection, it is important to detail the cleaning and disinfection program of the site. An appropriate technique is proposed (Figure 1). A triple disinfection, according to the definition proposed below by the authors was used during the start of a ZAC. Environmental data for surfaces are given (Figure 2) before and after disinfection.
The purpose of the initial cleaning, for classification, should be to prevent the clogging of filters by the excessive presence of particles when the system is in operation and to allow the classification system, the latter confirming the dustiness of the the air clean room, not necessarily microbiological contamination. Additional messy work may be justified if there are problems with the integrity or performance of the system, in fact, formal protocol-driven thorough cleaning and clean room maintenance may be required. . Cleaning consisting in removing construction work debris, pieces of cardboard and anything which is not necessary followed by vacuuming and wet wiping of all surfaces, with approved disinfectants, utensils and buckets, should be sufficient. A summary is given in Figure 3.
For more information, you are advised to consult the standard ISO 14644-5, Cleanroons and associated controlled environments – Part 5: Operations: 2004, Stages of building-related cleaning program.
After disinfection program established, it is important to follow these recommendations to properly maintain the environment during routine operations.
→ No cleanup should take place in ZAC when operations open phase and / or environmental monitoring is in progress.
→ Parts separated by ground lines, distinguishing two classes in the same room must be cleaned and undergo environmental monitoring according to the expectations of the strictest of the two classes.
→ Do not use the solutions and equipment recommended for the less stringent class to clean an area with a stricter class.
At a minimum, the following points should be taken into account when qualifying and classifying ZACs to be in accordance with the ISO14644-2 standard, Cleanrooms and associated controlled environments – Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1: 2000:
• particulate concentration limits, as used to classify clean rooms.
• Particulate counts are usually performed in operation, but can also be performed “as built” or at rest(4,5).
• Air flow rates or air velocities, which confirm the rate of hourly change by measuring air velocities to ultimately determine average ZAC speeds and renewal rates. (4,5)
• Differential pressures. (4,5)
The following tests are recommended to ensure that the HEPA filters behave as intended:
• Integrity and efficacy tests of HEPA filters using aerosols of 0,3 μm particles of polydispersed DiOctylPhthalate (DOP) or Poly Alpha Olefin (PAO). (4,5)
• Qualification of laminar airflow or Microbiological Safety Stations, if necessary. (4,5)
• Airflow visualization test or “smoke test” as validation element. (4,5)
There is a major difference between a leak test and a filtration efficiency test. A leak test is regularly scheduled to detect leaks in the media, at the support or at the joint. The HEPA filters are aerosolized with droplets whose average particle size is less than 1 μm but greater than 0,3 μm. The aerosol is introduced upstream of the filter and the filter is scanned on its downstream face at an approximate distance from 2,5 to 5 cm. The downstream leak being appreciated by the percentage of the upstream challenge, any reading equivalent to 0,01% is considered as representative of a significant leak. An effectiveness test is a general test used to ascertain the category of the filter. A HEPA filter has a minimum efficiency of 99.97% retention of particles larger than 0,3 μm (6). The efficiency of the filter will increase when the filter accumulates particles and will be the least effective when it is new or when it will leak.
In addition to push air through HEPA filters to reduce particle contamination in the air to meet the classification of the BIA, the system must also be capable of maintaining a sufficient pressure differential between the various BIA different classifications. According to the GMP in progress, there must be appropriate separations between different operations and ZAC. This is provided by the maintenance of pressure differentials between the different classified areas of a CAA. In aseptic manufacturing, the idea is to maintain a pressure cascade in order to protect the core area where aseptic activities are carried out, which has the strictest class in comparison with adjacent less critical classes, by maintaining a pressure differential of 10 to 15 Pascals between both areas with different classifications and unclassified areas. (7) The pressure differential must be sufficient so that the airflow removes particles and contaminants from the most critical area, so that these do not circulate near the doors, under the doors, or around the doors of a class A cleanroom when they are open. A pressure differential of X 5 Pascals (0,02 lnWC) is recommended between two adjacent areas with the same classification if one of them requires a higher level of cleanness. (8) The image in Figure 4 represents an aseptic manufacturing area with an ISO 5 laminar airflow in an ISO 7 room used for aseptic filling operations. The ISO 7 filling room is adjacent to an ISO 8 corridor. The areas adjacent to the corridor are also ISO 8 and are considered transit areas. Transit areas are designed as airlocks for equipment, staff, and products and are typically used for gowning and for bringing in disinfection utensils. To maintain the pressure differentials as provided for in the guides, the filling room was regulated at a pressure of X 30 Pascals 0.12 InWC. The pressure in the adjacent corridor was reduced relative to the filling area to X 18 Pascals 0.07 InWC in order to maintain a pressure differential of X 12,5 Pascals 0.05 InWC between the different areas with different classifications. The pressure in the transfer areas (disinfection airlock, equipment airlock, staff airlock) was additionally reduced by X 5 Pascals 0.02 InWC for a final pressure of X 12,5 Pascals 0.05 to avoid air with a higher dust content coming from a non-classified area from mixing in the corridor with cleaner ISO 8 class air, while remaining compliant with GMP requirements.
4 figure above describes an ideal situation pressure in parts. Like many things, more does not always mean better. Increasing the pressure of the parts beyond what is described is not recommended. Differential pressure too high result in extremely high and uncomfortable noise level and which can make it difficult to open or close the doors.
When the pressures are regulated at the recommended levels, the rooms can lose their pressure because of a mechanical failure. Pressure is then outside the limits with possibly a pressure reversal, which is most frequently due to poorly closed doors or doors intentionally left open to allow the passage of equipment or to facilitate communication. According to the FDA guide, Sterile Drug Products Produced by Aseptic Manufacturing, the time during which a door can remain open must be strictly controlled.
This guide goes as far as saying that differential pressure alarms must be documented and that deviations beyond threshold values, including alarm delays that exceed specifications, must be investigated. (9) It is important to establish alarm delays, otherwise there could be an excessive number of non-critical events, which would not justify a complete investigation. However, it could be a good idea to analyze this type of information and to see if corrective actions should be undertaken.
As with CTA shutdowns, sites need to determine how long a door can remain open without impacting the pressures. For lack of a better vocabulary, we speak of a “closing of doors” policy. In addition to establishing a time limit during which doors may remain open, it is also suggested to establish a time limit during which pressure differentials may remain outside established limits without warranting an impact analysis. on the product. Not having these two time limits could result in a significant increase in the number of investigations due to deviations of a few seconds. This would result in a considerable workload for the person (s) responsible for writing and dealing with these discrepancies.
If the site tracks the pressures of the parts with “Magnehelic” gauges, it is good to make sure that the manometer is in a place accessible to the operators to avoid them having to leave the zone or to use a scale to read this manometer. Finally, it is better to avoid setting too tight limits with non-digital indicators. It is simply impossible to make too fine readings with a “Magnehelic” because of the display format.
Temperature and humidity
The control of temperature and humidity during production operations is required to ensure the stability of the operating conditions but also for the comfort of personnel, prevention of static electricity and microbiological control.
Normally the temperature should be maintained at 20 ° – 22 ° C and relative humidity at 30 – 60% (16), with relative humidity levels up to 65% in some Guides (10). Although a temperature of 20 ° – 22 ° C is recommended, a temperature of 16 ° – 20 ° C is typical in areas where a completely covering aseptic workwear is required, since the multiple layers of the outfit add stress. additional to the operators. Aseptic dress may include an eye mask, nose and mouth mask, hood, coveralls, overboots, sterile sleeves and several pairs of gloves during aseptic procedures.
Improve operator comfort, keeping the temperature of the room acceptable when they are dressed, improves the probability of well respect the dressing procedures and prevent operators sweating or shivering with the result that they disseminate more particles. The sleeves are in gloves, masks or goggles do not fog, face masks stay in place and zips / buttons remain attached.
Procedures must be in place to handle instances of temperature or humidity deviation, as for pressure differentials and air handling unit faults. It is possible to tolerate a few short deviations which may occur because of a power cut or equipment stoppage. If possible, provide for a period during which a deviation is momentarily tolerated before actions are undertaken. Temperature cannot have the same consequences on the environment as deviations in humidity.
The temperature can impact the products or raw materials, however, humidity deviations can cause excessive condensation on floors, walls and ceilings especially when they are accompanied by increases in temperature. If this occurs, it is imperative to consider that this is a major event and the BIA must be disinfected accordingly. The moisture appearance gives microorganisms the environment they need and creates a dangerous situation for the environment in terms of alert levels overruns and action.
The answers to the major events of situations should be detailed in the cleaning and disinfection of premises. An action is not always necessary, provided that there are acceptance limits and validated procedures for CTA stops and pressure differentials differentials. When an event warranting action takes place, the rooms must be insulated with restriction of access of staff and additional dressing precautions to avoid contaminating adjacent areas. The BIA should be a triple disinfection after the occurrence of a major event and be an environmental monitoring prior to recovery. New clean rooms must meet the standard requirements of ISO 14644-2, however, the cleaning after the work is more about the particle removal for the classification rather than microbiological control. The triple disinfection before the resumption of aseptic activities is necessary as well as environmental monitoring and decision making by the quality on the basis of microbiological results.
1. Anderson C. and Lloyd B. (2014) Evaluation of Controlled Manufacturing Environments following an Air Handling Unit Shutdown. Pharmaceutical Engineering. 34 (1).
2. International Standard (ISO) 14644-2, Cleanrooms and
2: 14644 – 1: 2000: XNUMX – XNUMX.
3. PDA 70 Technical Report, Fundamentals of Cleaning and
Disinfection Programs for Aseptic Manufacturing Facilities (October, 2015)
4. International Standard (ISO) 14644-2, Cleanrooms and
associated controlled environments, Part 2: Specifications for testing and monitoring To Prove continued compliance with ISO 14644-1. (2000).
5. International Standard (ISO) 14644-3, Cleanrooms and
associated controlled environments, Part 3: Test methods. (2005).
6. FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Manufacturing -Current Good Manufacturing Practice. Sep. 2004. p 9.
7. FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Manufacturing -Current Good Manufacturing Practice. Sep. 2004. p 7.
8. Schneider, RK (2012) Why do Cleanrooms Fail to Meet Owners Expectations; Controlled Environments. April 2012.
9. FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Manufacturing -Current Good Manufacturing Practice. Sep. 2004. p 7.
10. International Standard (ISO) 14644-4, Cleanrooms and
associated control environments, Part 4; Design, Construction and start-up: 2001. p 32.
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