Smoke Study Mistakes and Solutions in Pharmaceutical Cleanrooms

One of the most essential qualifications performed within sterile pharmaceutical manufacturing facilities is the execution of smoke studies (airflow visualization studies). These prove by visual verification that the airflow produced protects the sterile products during manufacturing, filling and during any aseptic activity.

Due to the publication of the EU GMP Annex 1 (2022), there have been many updates to the expectations of the regulatory authorities regarding these smoke studies. Inspectors now require that pharmaceutical companies perform their smoke studies and demonstrate that the airflow will consistently remain effective over the course of routine operations (while a user is operating equipment).

In my experience, the HVAC performance of the facility itself is rarely the sole reason for a failure. More commonly, failure results from the lack of a plan, the study being executed in unrealistic conditions or due to a lack of documentation. Smoke studies should be designed to answer a simple question; "Does the airflow consistently protect the product throughout the entire manufacturing process?".

What is Smoke Study?

Smoke studies are demonstrations of airflow that visually illustrate the path taken by air and its effect on product sterility. They are conducted using a non-toxic or otherwise harmless smoke generator in a controlled environment to assess the air flow characteristics in a pharmaceutical cleanroom.
Each smoke study is evaluated for:

• The presence of unidirectional airflow.
• How quickly or slowly air is recovered once it is removed from critical areas or processes.
• Airflow velocity (velocity of air moving past an object).
• Obstructions to the flow of air within critical areas.
• Presence or absence of turbulence in the vicinity of critical areas.
• Protection of exposed sterile products from contamination due to airflow.

Unlike general environmental monitoring where contamination is detected after it occurs, Smoke Studies are used to identify airflow issues that could lead to contamination.

Importance of a Smoke Study

The air movement through a facility is a critical control measure for preventing contamination while manufacturing sterile products.
A Smoke Study confirms:

• HEPA filtered air reaches all critical areas in a timely manner.
• First air at exposed product locations is being maintained continuously.
• The actions of personnel do not disturb the airflow needed to protect the exposed product.
• The locations of equipment do not create turbulence.
• Return air systems effectively remove contamination from the facility.

Smoke Studies also provide evidence that contributes to cleanroom qualification, media fill validation, facility modification and regulatory inspection completion.

Regulatory Expectations

There are numerous international regulations that require creating airflow visualization studies. Regulatory authorities generally expect that the results of airflow visualization studies use smoke studies to demonstrate the following types of information:

• Dynamic operation
• Representation of the actual processes being used
• Worst case scenarios
• Adequate documentation via video
• Scientific analysis
• Risk based assessment

During sterile manufacturing inspections, inspectors frequently require copies of the smoke visualization videos to provide them with evidence of contamination control methods being employed.

Common Smoke Study Mistakes

Organizations use the analysis of the most frequent mistakes of common smoke studies to improve study quality and regulatory compliance.

1. Performing Studies Only Under Static Conditions

Conducting a smoke study in an empty room without an operator or equipment moving. Nothing about manufacturing operates in a static condition.
A dynamic smoke study will include:

• Equipment moving
• Operators moving
• Materials transfer
• Doors opening (if applicable)
• Routine intervention

From my previous experience, I would see good airflow in an empty room, but once the normal manufacturing conditions began, I could see the airflow become turbulent.

2. Ignoring Worst-Case Conditions

Only testing smoke studies under normal operational conditions. Testing smoke studies under worst-case conditions should occur and can include:

• Maximum number of operators
• The longest equipment configuration
• More than one operator/helper doing a routine intervention at the same time
• The largest package product configuration
• Maximum amount of material in the equipment

Testing under normal manufacturing conditions will give limited confidence on controlling a contaminated environment.

3. Incorrect Smoke Generator Placement

Introducing smoke from a location that does not match where real contamination may happen, thereby producing misleading airflow patterns. The smoke generator should reflect real-life sources of contamination found in the following areas:

• Your hands as an operator
• Equipment surface areas
• Location of transfer points for items or material
• Location of open containers
• Critical processing area

Having proper placement of the smoke when conducting your tests will improve the scientific value of the results you will be collecting.

4. Excessive Smoke Generation

Producing excessive amounts of smoke will not yield more accurate results. Heavy smoke clouds can have several negative effects on an experiment:

• They may disrupt airflow, thereby obscuring any visualization available
• They may create artificial turbulence or velocity misrepresentation
• They can distort the airflow

The ultimate goal is to create a visualization of airflow, not to overwhelm it with smoke. Controlled reduction of smoke production will yield more beneficial results.

5. Poor Video Documentation

Regulatory agencies want records to be of good quality. The most common issues with documenting via video are:

• Bad camera position
• Insufficient lighting
• Recording was not completed
• Did not include a stamp with time
• Short length of recording

A good quality recorded video clearly demonstrates air movement (airflow) before a critical event, during a critical event and after a critical event.

6. Failing to Evaluate Operator Interventions

Operators are the biggest contributor to contamination in aseptic processing. Smoke studies should include all interventions to the aseptic process including:

• Putting things away
• Loading parts
• Moving their gloves
• Disposing of goods
• Adding stoppers

By including operators, determinations may be made as to whether there are any interruptions in the first air delivered to the critical surfaces.

7. Ignoring Airflow Obstructions

Changes in equipment can also change the airflow. Common airflow obstructions include:

• Large filling machines
• Cameras
• Sensors
• Product containers
• Temporary tools

Every time there is an installation, the impact on airflow should be analyzed.

8. Inadequate Protocol Design

Poorly designed protocols frequently yield incomplete studies. Properly designed protocols should provide:

• Study goal definition
• Testing locations
• Smoke generator specifications
• Acceptance criteria
• Intervention scenarios
• Data collection methods
• Individual responsibilities

Without appropriately defined protocols studies become inconsistent and often difficult to interpret.

9. Incorrect Interpretation of Airflow

Not all visible turbulence is necessarily unacceptable airflow. Investigators should distinguish between:

• Localized turbulence that is acceptable
• Recovery of airflows
• Interruption of first air
• Risk of product exposure to contamination

Investigators should interpret airflows based on contamination risk rather than just on visual indicators.

10. Treating Smoke Studies as a One-Time Activity

Some organizations only perform smoke studies when qualifying a facility. As airflow is modified due to the following conditions, airflow should be retested each time.

• Modifications to equipment
• HVAC system changes
• Renovation or modifications to facilities
• Modification to processes
• Major maintenance
• Introduction of a new product

Validation status is retained by conducting periodic assessments of airflow.

Root Causes Behind Smoke Study Deficiencies

System-wide problems often result in multiple instances of inadequate or faulty smoke study results. Traditional system-wide issues can stem from the following:

• Inadequate contamination control program
• Insufficiently trained personnel in smoke testing procedures
• Weak risk assessments for planned smoke tests
• Poorly prepared smoke test protocols
• Limited knowledge of airflow principals
• Inadequate planning
• Lack of resources

By identifying and addressing the systemic issues, the frequency with which individual studies fail can be reduced.

Solutions for Effective Smoke Studies

There are many proven ways that organizations can enhance their study quality through best practices.

1. Develop a Risk-Based Protocol

Protocols should be developed with the use of Quality Risk Management principles. Risk-based testing provides stronger scientific justification by focusing on:

• Critical processing locations
• High-risk activities
• Worst-case scenarios
• Product exposure points

Risk-based testing provides stronger scientific justification.

2. Simulate Regular Manufacturing Operations

Smoke studies should be as similar as possible to normal production due to:

• Normal batch processing
• Movement of equipment
• Different worker activities
• Material transfer
• Cleaning activity

Producing realistic simulations provides stronger evidence of study results.

3. Train Personnel Thoroughly

Administration of a smoke study requires personnel to know:

• Airflow
• Contamination control
• Placement of camera
• Operation of smoke generator
• Regulatory expectations

Trained personnel can provide dependable study results.

4. Improve Video Quality

Use:

• Multiple cameras
• High definition recording
• Adequate lighting
• Continuous recording
• Visible timestamps

Providing video that is clear and well documented will increase the likelihood of interpretable studies during audits.

5. Conduct a Cross-Functional Review of Smoke Studies

Interpretations of a smoke study should include input from:

• Quality Assurance
• Validation
• Production
• Engineering
• Microbiology

Having individuals conduct cross-functional reviews of the study data will reduce individual bias as well as provide better technical correctness.

Role of Smoke Studies in Contamination Control Strategy

Contamination control strategies will include smoke studies as a part of their compliance with EU GMP Annex 1. They will provide information regarding:

• Airflow design
• People working in the areas
• Equipment arrangement
• Aseptic process methods
• Improvements in processes

As such, they should be part of environmental monitoring programs, media fill studies, cleaning validation and facility qualification.

Preparing for Regulatory Inspections

The requirements for the FDA and European inspections start with the submission of smoke study protocols. Other requirements may include raw video, study report, investigation records, CAPA documentation and risk assessments.

To ensure that the current day's operations are consistent with validated airflow conditions, it is recommended that facilities periodically review historical smoke studies.

Best Practices for Successful Smoke Studies

General good practices for successful smoke studies are typically followed by an organization that has a mature contamination control program.
Recommended Best Practices:

1. Conduct studies under dynamic conditions.
2. Challenge the worst potential interventions.
3. Use scientifically justified smoke generation techniques.
4. Record high-quality video from multiple angles.
5. Evaluate first air protection continuously.
6. Review airflow as it relates to changes made to equipment or processes.
7. Integrate smoke studies into your contamination control strategy.
8. Train personnel on airflow visualization techniques regularly.
9. Have a complete record of documentation.
10. Periodically trend findings and implement CAPA as needed.

Smoke studies serve a much greater purpose than just meeting regulatory requirements, they visually demonstrate how cleanroom airflow protects sterile product through manufacture. While many organizations seem to place more emphasis on producing acceptable videos other than actually identifying contamination risks before they impact product quality are experienced pharmaceutical professionals.

I have found that the more successful pharmaceutical manufacturers tend to use smoke studies more as a continuous improvement tool and less as a qualification exercise. By performing realistic, risk-based studies that are well-documented and scientifically validated, manufacturers can further develop their contamination control strategy; improve the reliability of their aseptic process and confidently provide evidence of regulatory compliance when needing to during a regulatory inspection.

Regulatory References

1. EU GMP Guidelines Volume 4, Annex 1: Manufacture of Sterile Medicinal Products (2022)
https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en
2. FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice
https://www.fda.gov/media/71026/download
3. WHO Good Manufacturing Practices for Sterile Pharmaceutical Products
https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/gmp

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