This article was published in Pharmaceutical Technology Europe, Volume 30, Issue 5, May 2018.
Airflow visualization studies (i.e., smoke studies) are conducted to confirm unidirectional airflow patterns within an aseptic processing facility. Static studies are intended to document that the airflows within the Class A/ISO 5 zones are unidirectional and cascade out to the zones with lower cleanliness requirements. Dynamic studies should document that airflow within the Grade A/ISO Class 5 filling lines is unidirectional and sweeping down and away from sterile equipment surfaces, container/closure systems, and product. Dynamic studies work to confirm that facility and equipment design, equipment operation, and personnel aseptic manipulations (i.e., interventions) do not disrupt the “first air” (i.e., air exiting the high-efficiency particulate air filters within the Class A zone essentially particle free, in a unidirectional manner) to critical areas where sterile surfaces, materials, and products are exposed.
Inadequate airflow (e.g., turbulence due to line design issues and first air disruption during interventions) in the critical Grade A zones, where sterile products and components are exposed, could lead to the introduction of contaminants into drug products as they are being filled and stoppered, posing a risk to product sterility.
A product contamination risk can result if first air is disrupted by passing over non-sterile surfaces of equipment, tools, components, or operators on its way to exposed sterile product, components, and equipment. Any viable or non-viable matter on these non-sterile surfaces can be dislodged and introduced as contaminants into the sterile drug product.
A successful smoke study report will include a thorough analysis of the study, justifying that satisfactory airflow under static and dynamic conditions was achieved. If the smoke study finds unacceptable air flow (e.g., first air disruption by equipment operation and/or personnel interventions) or turbulence, an investigation should identify the root causes and recommend actions to be taken (e.g., filling line or equipment modification, change in personnel behavior/aseptic technique, adjustment of air velocities).
Turbulent airflow may be acceptable in closed systems, such as an isolator, provided that studies demonstrate that acceptable particulate levels can be maintained. Smoke study video recordings are considered data that should be maintained as any other data generated on site.
GMP requirements
Although the FDA good manufacturing practice (GMP) regulations do not specifically refer to smoke or airflow visualization studies, FDA has issued observations using FDA Form 483 and warning letters citing the lack of smoke testing or inadequate smoke testing to establish appropriate airflow that reference the following sections of 21 Code of Federal Regulations (CFR)Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals (1):
211.113(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 any sterilization process.
211.63 Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
21 CFR Part 211.113(b) is generally cited when the video shows operator activities are contributing to turbulence or the true air flow cannot be demonstrated based on the poor placement of the smoke source and camera angle.
21 CFR Part 211.63 is generally cited when the video shows the line design/equipment placements are contributing factors to turbulence.
Elements of a smoke study protocol
Airflow smoke studies should be performed during qualification of new facilities, following changes in facilities impacting the sterile core (e.g., air-handling systems or aseptic processing equipment), and following changes/improvements in aseptic activities/interventions.
The smoke study protocol should clearly define the objectives, responsibilities, tools to perform the study, and acceptance criteria for static and dynamic conditions.
To ensure a strong smoke study, the following elements should be included in the plan:
- Responsibilities for developing, implementing, reviewing, and approving the smoke studies
- A floor diagram of each filling room including details within the filling line and the equipment, carts, etc. in the support areas surrounding the filling line (The floor diagram can mark the general position where the operator will perform each type of intervention, the general position of the smoke source and camera position(s) to effectively capture each intervention. These floor diagrams are helpful to identify to the inspector where the intervention is being performed and the location of the camera because some smoke study views are too close up to clearly show where on the line this is occurring.)
- Type of smoke generators to use and smoke source (e.g., water for injection or deionized water heated and combined with liquid nitrogen or dry ice
- Acceptance criteria, as applicable (see following section)
- Actions to take if acceptance criteria are not met (e.g., an investigation to determine the root causes and implementing a corrective action and preventive action [CAPA] to eliminate a recurrence of airflow disruption. Note that after implementation of the CAPA a new smoke study is performed.)
- The process for identifying each intervention shown on the video (e.g., a placard or slide can precede each intervention and/or narration as each intervention is performed).
Acceptance criteria include the following:
- Static conditions within the Grade A filling lines show unidirectional airflow patterns sweep down and/or away from the exposed product, product contact packaging components, and product contact surfaces.
- Dynamic conditions within the Grade A filling lines show unidirectional airflow remains stable during interventions with no disruption of first air to critical areas where sterile surfaces, materials, and products are exposed.
- Air from outside the critical Grade A/ISO Class 5 area is not drawn into the critical zone during interventions.
- Sufficient smoke should be generated to allow the smoke to merge with the airflow and visually display its direction.
- The smoke source is positioned to allow sufficient smoke to enter the airflow over the operator and tools (e.g., forceps) during the intervention to visualize the impact of this activity on the airflow. As the operator and tool moves within the Grade A filling line during the intervention, gradually move the smoke source to follow these activities to allow continuous visualization of the impact of the operator’s activities to the first air.
- Do not generate excessive smoke. The density of the smoke may prevent a clear view of the operator, the intervention, and impact on airflow.
- All interventions occurring in actual filling operations and simulated in media fills must be accurately simulated in smoke studies. Be prepared to provide a master list of all known interventions for each drug product filling operation by container/closure system on each filling line configuration and the supporting smoke study or smoke studies.
- Include ergonomic considerations; if multiple personnel of different stature (e.g., short vs. tall) perform the same intervention in a different manner and/or require different tools or aids, include this in the smoke studies.
- All filling line and filling room equipment configuration and placement represent those utilized in current routine processing and media fills. All applicable standard operating procedures and any other reference material that may be necessary to verify the accuracy of the room configurations, equipment operation, and personnel intervention should be referenced or attached, as necessary.
Executing the smoke study protocol
Smoke studies are generally not a routine event performed at a recurring fixed timeframe in the same manner. New or additional smoke studies may involve changed or different filling rooms, different interventions, new or different smoke sources, different video cameras, or different personnel, for example. Given these variables and the cost, time, resources, and effort necessary to carry out a successful smoke study, it is best to carry out a rehearsal of these activities to identify any unforeseen barriers or limitations.Consider the following:
- Determine where and how the smoke source(s) will be placed within the filling line. Based on space and design limitations, different types/sizes of smoke sources may be needed.
- Practice how the person holding the smoke source will follow the operator performing the intervention to ensure the smoke is always correctly positioned. Common errors occur when the smoke source is not held over the operator as he performs the intervention, not moving the smoke source as the operator moves, and having the smoke source in continuous motion, thus preventing a clear view of the impact of the operator on airflow.
- Determine the positions for the camera to capture the operator performing the intervention in its entirety. For some interventions, based on the filling line design and space limitations, it may be necessary to video the activity from multiple angles to clearly show the impact of the intervention on the airflow.
Ensure the persons responsible for taking the video have the skills to consider how variables such as distance, angle, lighting, camera movement, and other variables can impact the video to minimize the number of re-shoots necessary to capture the intervention and its impact on airflow clearly. The video shoot should have a director to manage and control all the personnel involved in performing the interventions, positioning the smoke source(s), and the videographer(s) to ensure the event is performed accurately, captured clearly and completely on video or, if not, repeated.
Large pharmaceutical companies with numerous and different types of aseptic filling operations and environmentally controlled support rooms may have communication and coordination challenges under some situations, such as when numerous smoke study teams work simultaneously, at times, around the clock to complete all smoke studies during the firm’s plant shutdown or when private smoke testing contractors and/or personnel from other corporate divisions or sites are brought in to assist in the smoke studies. Managing these diverse groups, some of which may have never worked together and may have differing views about smoke studies, will require close quality assurance (QA) oversight to ensure consistent implementation of the smoke study protocols.
Smoke study final report
The smoke study report review process should not lose focus that a key element of the review is the video itself and not principally the unexecuted protocol that contains all the expectations. Upon execution, if the video does not clearly and unequivocally show the adequacy of airflow when interventions were performed accurately on the filling line set-up as currently used, acceptance criteria have not been met. The review of all the static and dynamic smoke study videos should involve subject matter experts (SMEs) from the various departments involved to ensure all depictions in the videos accurately represent current practices.
The final QA review to assess compliance with acceptance criteria can be challenging and may benefit by having additional reviews by other QA and/or SMEs not actively involved in producing the smoke study. Having a separate set of reviewers to critically review and, as necessary, challenge any views that are not clear or subject to more than one interpretation, may pick up weaknesses not apparent to the initial reviewers, which are the type of weaknesses that may be detected by a regulatory inspector.
Non-airflow issues evaluated in smoke studies
Static and dynamic smoke study videos may provide many different views and close-up views within the sterile core that are not visible or clearly visible through the view windows or cameras into these areas. These views can identify other GMP issues for a regulatory inspector to pursue. For example, a clear view of the aseptic technique used in complex interventions could lead to further review of the technique for reproducibility as practiced currently. When viewing the condition of gowning and compliance with gowning requirements, any differences with current gowning practices will be evaluated. A view showing the facility and equipment complexity of design, age, and surface condition (e.g., excessive number of scratches or deep scratches/gouges, deterioration, rust) can lead to questions about how these surface conditions may impact the ability of current practices to consistently and effectively clean, sanitize, and sterilize these surfaces. Questions about preventive maintenance and part replacement practices in these critical areas may also be pursued.
QA review of the smoke studies should not be limited to airflow issues but to the entire content of the video to ensure all GMP issues have been addressed, including those not directly related to airflow.
Conclusion
As is the case with media fills, smoke studies only document the conditions occurring at the time the studies were performed. QA and production department oversight should ensure the controls displayed in the smoke studies represent current practices used by all the other personnel performing similar activities but not involved in the smoke studies. Systems should be in place to detect, investigate, correct, and prevent recurrence of any variance from these controls and, as necessary, repeat the smoke study.
This type of smoke study review and preparation can make the regulatory inspector’s review of smoke studies a relatively uneventful and routine step of the inspection, with the inspector generally satisfied with the videos.
Reference
1. CFR Title 21, Part 211.
About the author
Manuel M. Garza is a principal consultant with PAREXEL Consulting, a subsidiary of PAREXEL International, [email protected].
Article details
Pharmaceutical Technology Europe
Vol. 30, No. 5
Pages: 38–41
Citation
When referring to this article, please cite it as M. Garza, “How to Plan Smoke Studies,” Pharmaceutical Technology Europe 30 (5) 2018.
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