The Smoke Study is a fundamental element of the qualitative and quantitative analysis of an airflow. Air flow visualisation studies aim to demonstrate on the one hand the visual evidence of unidirectional air flows within an aseptic facility, and on the other hand the ability of the system as a whole to protect the product and critical areas through a constant flow of primary air from the absolute filters.
The need to control the maintenance of unidirectional flows is clearly stated in Annex 1:
4.14 Cleanrooms should be supplied with a filtered air supply that maintains a positive pressure and/or an airflow relative to the background environment of a lower grade under all operational conditions and should flush the area effectively. Adjacent rooms of different grades should have an air pressure difference of a minimum of 10 Pascals (guidance value). Particular attention should be paid to the protection of the critical zone. The recommendations regarding air supplies and pressures may need to be modified where it is necessary to contain certain materials (e.g. pathogenic, highly toxic or radioactive products or live viral or bacterial materials). The modification may include positively or negatively pressurized airlocks that prevent the hazardous material from contaminating surrounding areas.
4.15 Airflow patterns within cleanrooms and zones should be visualised to demonstrate that there is no ingress from lower grade to higher grade areas and that air does not travel from less clean areas (such as the floor) or over operators or equipment that may transfer contamination to the higher grade areas. Where unidirectional airflow is required, visualisation studies should be performed to determine compliance, (see paragraphs 4.4 & 4.19). When filled, closed products are transferred to an adjacent cleanroom of a lower grade via a small egress point, airflow visualization studies should demonstrate that air does not ingress from the lower grade cleanrooms to the grade B area. Where air movement is shown to be a contamination risk to the clean area or critical zone, corrective actions, such as design improvement, should be implemented. Airflow pattern studies should be performed both at rest and in operation (e.g. simulating operator interventions). Video recordings of the airflow patterns should be retained. The outcome of the air visualisation studies should be documented and considered when establishing the facility's environmental monitoring programme.
Observations and warning letters
From a regulatory point of view, regulators have repeatedly intervened through observations and warning letters, complaining about the absence of adequate tests documenting adequate airflow in both At Rest and In Operation conditions.
The observations and warning letters mention in particular: CFR 21 part 113 (b):
Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and sterilisation processes...where the operator interrupts the unidirectional flow by creating turbulent movement, or where, during testing, the angle of the chamber does not permit proper visualisation of the flow, or where the reagent source is positioned inefficiently.
Other observations report that:
- Smoke studies in Grade A hoods were not conducted under In Operation conditions
- No study was conducted to evaluate airflow during aseptic operations
- The Smoke Studies were not adequately documented
- The film does not adequately visualise the impact of turbulence/vortices on the product during In Operation operations
It would in fact be reductive to consider the smoke study in classified environments a mere control test. It is in fact a moment of investigation of the criticalities present in a process, which determines not only a series of possible corrective actions in the process studied but also the verification of the consequent implementation activities.
The smoke study initiates a kind of domino effect, in which an airflow control represents the primary process of subsequent checks and verifications.
The behaviour of cleanroom operators, their exact adherence to SOPs, their training and the quality of processes become verifiable precisely through the airflow visualisation test. In fact, inspection bodies often challenge tests that have not covered steps that are not directly related to air flows, such as the transfer of materials from adjacent areas.
Parameters to consider when performing the smoke study
The smoke study covers a number of parameters that are fundamental to its correct execution and to avoid any non-conformities that could alter both its success and the process under examination.
- Study of the layout/area under examination
- Study of ventilation system flow management
- Reagent used
- Volatility
- Persistence
- Visibility
- Equipment used
- SOPs and operator behaviour in compliance with them Humidity and temperatures according to reagent used Smoke angles/cameras
- Video footage
- The human factor
Each of these parameters, if not properly contemplated, can generate errors.
The layout: One of the most critical issues can be determined by an unsuitable layout of the area where the production process takes place. These areas should ensure a unidirectional flow and a good ability of the system to protect the product and critical areas.
Ventilation system flow management: The smoke study often highlights poor flow management, but not only that: it is a valuable aid in verifying pressure cascades to neighbouring areas and rooms of lower criticality.
Reagent: The choice of reagent is one of the decisive elements in the success of a smoke study and must be considered from several aspects.
Firstly, volatility. The right degree of volatility allows the reagent to be transported without altering the direction of the air flow. A low volatility value can result in a downward direction from the generator mouth, preventing a good visualisation of stagnant air flows in specific areas of the process. Similarly, the degree of persistence: low persistence may not be sufficient to complete visualisation. The balance between volatility and persistence is essentially related to the size of the area under analysis and the characteristics of the instrumentation used.
It is essential to define the right parameters to ensure that the smoke reaches the entire area under examination and that it is correctly free of any interfering elements that could compromise the study. The smoke generated must ensure that the critical area where the product is exposed is properly cleaned.
Last but not least, the tracer used must be non-toxic and free of corrosive capabilities that are harmful to personnel and the equipment and systems involved in the smoke study.
The smoke generator: Currently, smoke-generating equipment mostly use CO2, glycol solution, liquid nitrogen or deionised water.
The toxicity of CO2 and especially liquid nitrogen, as well as the complexity of their handling, make their use inadvisable. The glycol solution entails the need for thorough cleaning after the flue gas study.
The use of deionised water is therefore advisable, not only for its compatibility with the materials and the absolute safety of the operator, but also because, through a study of the above parameters, it ensures the success and effectiveness of the Smoke Study.
The smoke generator should have a degree of automation that favours the reduction of operator intervention within the area under analysis. Remote control of the test avoids the risk of operator disturbance. Accessories are also essential. Pipes of varying lengths as well as lances help to carry out the smoke study in the best possible way.
Relative humidity and temperature: Other parameters to be taken into account are the relative humidity and temperature of the air in the tested area: if, depending on the reagent used, the humidity is too low or the temperature too high, the visualisation is impaired.
Smoke angles: It is essential that the smoke is perpendicular or oblique to the airflow in order to accurately visualise the air configuration.
It is essential not to direct the tracer generation directly onto the area under examination.
Video recording: The most important result of a smoke study is the accurate video evidence that indicates the adequacy of the flows to the inspection bodies. Recording from several angles and with the right level of lighting can give the desired result.
Depending on the size of the area, at least three cameras should be used to capture the operations performed during the study from opposite sides of the area being examined.
The view of each opposing camera must be wide enough to capture the entire airflow. An incorrectly angled recording may not include the entire smoke curtain, operator manipulations or air flowing over the equipment.
In situations such as a biological safety cabin, with an interior of a Grade A classification and an exterior of a different classification, or passages/thresholds/doors between areas where the focus is on the directionality of the airflow, it is always advisable to have a moving camera to capture different angles. A single camera may be the best solution when the subject is a HEPA-filtered air supply within a classified room.
Adequate lighting is crucial for accurate video reproduction of the smoke study. Finding the balance is crucial: not too bright to cause glare or too dim to lose essential details. In both cases of recording angles and lighting, it is often useful to rehearse to fine- tune camera angles and lighting to verify that the originally intended smoke and airflows are being captured before performing the actual smoke study.
The human factor: Last but not least is the human factor. There is often a gap between operational procedures and their application, and it is this gap that represents one of the most important risks within a process. The smoke study is an essential moment to verify the gap between what should be done and what is actually done within the process. Its results are extremely useful to act on corrective actions and subsequent implementation activities.
Takeaways
In conclusion, the Smoke Study can be considered a true Process Study, where the
essential element is in fact the operating personnel and their actions within the classified area. What is derived from the Smoke Study is the essential need for personnel training and corrective actions on their behaviour and airflow in the area in question.
MyFog (registered trademark) by AM Instruments is a tool that AM's validation team performs smoke testing with. The MyFog system is the result of research and development by the company. With the standard remote control option, a single operator can manage the start/stop of the unit and the intensity and speed of smoke regulation. MyFog has an intuitive interface with a 2.8 inch touch screen, allowing the operator to have immediate diagnostics and display of key operating parameters.
