Smoke Studies

A review of the Form 483’s issued to the 45-registered and inspected 503B Outsourcing Facilities identifies that over 40% (n = 19) of the inspected facilities received one or more observations concerning inadequate smoke studies.

Common findings of the smoke studies included studies that were not performed under dynamic conditions, studies that do not adequately reflect the aseptic processes or operator interventions performed, inadequate studies including limited smoke, studies that were not recorded, not reviewed, and final summary of acceptance, and studies where turbulent air flow was identified.

Detailed findings from the From 483s include the following:

  • Dynamic Conditions, or not reflective of the firms processes:
    • Smoke studies were not performed under dynamic conditions to verify that operators and processing equipment do not alter or impede the unidirectional cascade of air from the HEPA filters to the ISO 5 laminar flow benches where sterile drug products are opened and manipulated, and to the rest of the ISO 7 clean room.
    • No smoke study procedure was used to evaluate your ISO 5 IV hood under dynamic conditions and no additional smoke studies have been conducted since the IV Hood was installed in 2009 [Note date of the inspection – August 2014].
    • Smoke studies were not conducted for the ISO 5 hoods; they were only conducted in the ISO 7 cleanroom with [redacted] present, which is not representative of routine aseptic operations with [redacted] operators.
    • A review of The Critical Manufacturing Area Smoke Test, completed 05/21/2014, found that the ISO 5 classified critical zones in each clean room were not evaluated under dynamic conditions with compounding equipment and components in place.
    • Smoke studies are conducted during [redacted]; however, these studies are handled in static conditions and do not show adequate coverage of the ISO 5 area or the ISO 7/8 entryway and pass through(s).
    • The firm’s in situ air pattern analysis (smoke studies) was not conducted under dynamic conditions, simulating routine production (i.e. compounding equipment in place and operations ongoing).
    • Clean room certification and smoke studies for the ISO 7 Cleanroom were not performed during the operation of the [redacted].
    • Smoke studies were not performed under dynamic conditions to verify that operators, processing equipment, or activities of the ISO 7 clean room do not alter or impede the unidirectionality of air from the HEPA filters to the [redacted] ISO 5 laminar flow benches where products are aseptically processes.
    • Smoke studies are not performed under dynamic conditions.
    • The smoke study was not performed under dynamic conditions to verify that the operator or activities in the ISO 7 cleanroom do not affect the unidirectional airflow from the HEPA filters in the ISO 5 hood where drug products are produced.
  • Inadequate Studies:
    • The smoke studies were not recorded to demonstrate laminar air flow during dynamic conditions.
    • No dynamic airflow pattern studies (smoke studies) have been performed in the [redacted] ISO 5 hoods inside your ISO 7 room where sterile drug products are formulated and filled.
    • Limited smoke was used and did not completely confirm uni-directional flow inside the filling line and all of its components.
    • Not all operators’ interventions were included such as multiple interventions conducted at the same time or line set-up activities.
    • Operators were observed standing directly in front of wall air returns but video failed to follow the smoke pattern at this area.
    • Operators were observed performing very slow movements while adding stoppers and opening [redacted] doors – unlike current practice observed during routine operations at the same line on 11/17/14.
    • The smoke studies are not reviewed by your personnel and there is no final report regarding the adequacy of the airflow.
    • The firm has no documentation of smoke studies conducted under dynamic conditions to indicate adequate unidirectional air control during sterile compounding.
    • Smoke studies do not indicate vertical laminarity of air flow from your ISO 5 vertical flow hood.
    • The smoke studies performed in the ISO 5 [redacted] area of SVP Line 1 are inadequate in that there is insufficient smoke to clearly show unidirectional air flow, the dynamic portion of the smoke study at the [redacted] included an operator who did not move, and the study did not include smoke near the window on the back side of holes that were open to the ISO 8 room in order to perform [redacted].
  • Turbulent Air Flow:
    • Smoke studies conducted on March 20111 2014 show turbulent and stagnant air within ISO 5 areas used to sterilize and fill drug product unit containers.
    • Video of the dynamic smoke studies conducted to demonstrate unidirectional airflow [redacted] located in clean room [redacted] showed considerable turbulent airflow when [redacted] was placed within the work zones of the [redacted] l

Performance Validation has significant experience in the planning, development, and execution of critical airflow visualization studies commonly referred to as Smoke Studies.  In one recent example, at a large Pharmaceutical Manufacturing Facility, Performance Validation was tasked with complete Critical Airflow Visualization/Verification Studies for an entire aseptic processing area.  The aseptic processing area consisted of fifteen separate areas that needed to be examined for critical airflow, including filling lines, lyophilization loading/unloading areas, locally controlled environments, and stopper processing equipment.  All spaces classified as Grade A were examined and verified as acceptable during dynamic and static conditions.

Have a question on Critical Airflow Visualization Studies or would like additional information on how Performance Validation can help you meet FDA expectations when documenting critical airflow?  Contact Dalton Pierson, Performance Validation’s Critical Airflow Visualization expert.

Previous Software as a Medical Device (SaMD): Clinical Evaluation and Validation
Next Current Inspection Trends From FDA Warning Letters