Airflow visualization studies (AVS) (also known as smoke studies) are an integral part of contamination control practices in GMP-controlled aseptic processing plants. As per regulatory guidelines such as the FDA’s 2004 Guidance on Aseptic Processing (here), USP <1116> (here), and PDA Technical Reports 13 (here), 22 (here), and 34 (here), these studies enable the measurement and qualification of unidirectional airflow (UDAF) systems. Their primary role is to demonstrate through visualization that the target air handling system can achieve the appropriate room-air quality to satisfy the room classification based on the production activity conducted in the space. Here’s a brief overview of regulatory requirements, optimal study design best practices, typical barrier system flaws, and key concepts related to general aseptic assurance processes.

Sterile drug manufacturing relies upon aseptic processing when terminal sterilization cannot be achieved. Maintenance of an aseptic environment by unidirectional flow of air, particularly in ISO 5 environments, is one of the cornerstones of aseptic assurance. Airflow visualization studies are important tools for ensuring such environmental controls.

 

First, the guidance and references:

The FDA Guidance for Industry: Sterile Drug Products Prepared Through Aseptic Processing – Current Good Manufacturing Practice advises that airflow visualization must be:

  • Done to prove unidirectional flow and particle sweep away from the critical zone.
  • Performed during initial facility qualification and requalification.
  • Performed under static and dynamic conditions to enable the comparison of its effect on equipment and humans.

 

The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use: Annex 1  (here):

  • The outcome of the air visualisation studies should be documented and considered when establishing the facility’s environmental monitoring program.

 

PDA Technical Reports state:

  • TR 13 – Fundamental of an Environmental Monitoring Program: Where an AVS can support and feed into a robust EM program
  • TR 22 – Process Simulation for Aseptically Filled Products: Ongoing process evaluation periodically challenges the process and assess a state of control
  • TR 34 – Design and Validation of Isolator Systems: Highlights integration with isolators and RABS as issues that weaken the integrity of airflow

 

USP <1116> Microbiological Control and Monitoring of Aseptic Processing Environments states:

  • USP <1116> positions aseptic control within a risk-based dynamic process and highlights the importance of airflow visualization within environmental qualification and process monitoring.

 

The objectives of an AVS are to study airflow and eddies and demonstrate minimal or no turbulence in ISO 5 (Grade A) regions. This ensures a safeguard (one of many needed) of crucial processing areas protected with continuous first air. Additionally, under dynamic conditions, a properly executed AVS will demonstrate the impact of interventions, equipment configurations, and processes on the critical processing areas. Any trouble spots identified will allow the user to mitigate them before they impact product sterility.

Design an AVS with key principles:

  • Scope: Ensure that the AVS is a holistic analysis of the manufacturing environment. What should be captured depends on the equipment and aseptic process. For example, a filling room with a Biosafety Cabinet, RABS, and an Isolator should have a custom AVS approach. Caution against relying on a templated AVS – there are always specific nuances which will require a custom approach.
  • Acceptance Criteria: An acceptance criterion may not necessarily be zero turbulence; set an acceptable criterion that supports the equipment and process and is aligned with regulations.
  • Equipment: The department must be familiar with terms and principles to execute comprehensive AVS. For example, Neutral Buoyancy, Tracer Injection, Ejection Velocity, and Settling Velocity are some of the key characteristics an organization must be familiar with to successfully execute an AVS and be able to discuss and explain the study to auditors. The type of smoke, video equipment, and lighting all play an integral role in executing a successful AVS.
  • Flow Path: Under static and dynamic conditions, what areas will be captured in the AVS.

 

The summary report should document air velocity, height of ejection, working height, criticality of any reflux (if any), and eddy or stagnant areas of concern. Be sure to know what “good” really looks like.

Reviews of AVS have led to some common observations. Again, be sure to know what “good” really looks like:

  • Airflow abnormalities
  • Turbulence at the back of equipment or staff, or air stagnation.
  • Re-entrainment from improperly positioned air returns or penetrations.
  • Vortices near RABS gloves or doors (e.g., RTP, transfer hatch).
  • Inadequate airflow recovery following movement or interventions.

 

Integrate the AVS into the Aseptic Assurance Program. Smoke studies should be incorporated into:

  • Initial qualification (IQ/OQ) of cleanrooms and critical equipment.
  • Routine requalification (typically annually, or after changes).
  • Training personnel and simulation exercises for interventions.
  • Investigation of deviations and CAPA development when airflow is implicated.

 

Visualization of airflow is not a regulatory checkbox, but a critical means of ensuring environmental control necessary for aseptic manufacturing. A well-conducted study provides useful knowledge regarding system performance, enables risk evaluations, and enhances product quality and ultimately – patient safety.

If ejection velocity, settling velocity, neutral buoyancy, manifold orientation, orifice size and location are terms you aren’t familiar with or if you have questions relating to the above topic, Lachman Consultants can help you! Please contact LCS@lachmanconsultants.com for support with this critical study.