Ensuring Reliable Spray Pattern and Plume Geometry Validation in Oral Sprays Manufacturing

All equipment used in this process validation must be duly qualified and validated for its intended use and performance specifications. Equipment qualification (IQ/OQ/PQ) is assumed to be completed prior to this process validation.

Desired Attributes of Spray Pattern and Plume Geometry in Oral Sprays

To meet the QTPP and deliver consistent therapeutic outcomes, the spray pattern and plume geometry must exhibit specific attributes:

• Uniformity: Even distribution of droplets across the spray pattern area to ensure accurate dosing.
• Reproducible plume angle: Consistent plume spread to guarantee targeted delivery within the oral cavity.
• Fine droplet size distribution: Optimal droplet sizes compatible with mucosal absorption and patient comfort.
• Minimal drift or spray deviation: Reduced variation between actuations for dose consistency.
• Stable spray characteristics: Maintenance of spray attributes over the product’s shelf life and varying environmental conditions.

Impact of Spray Pattern and Plume Geometry on Quality Target Product Profile

Spray characteristics directly influence several QTPP elements:

• Dose uniformity: Variations in spray pattern size or droplet distribution can alter dispensed drug quantity.
• Therapeutic efficacy: Poor plume geometry may lead to suboptimal drug deposition and absorption in the oral mucosa.
• Patient compliance: Consistent spray feel and delivery improve patient acceptance and adherence.
• Product stability: Uniform spray performance over time supports ongoing product robustness.

Identifying Critical Quality Attributes (CQAs) for Spray Pattern and Plume Geometry

Key CQAs must be defined and controlled during validation to ensure compliance and product performance:

• Spray pattern diameter and shape: Critical for ensuring proper coverage and dose dispersion.
• Plume angle: The angle formed by the spray plume affects the directional delivery of the drug.
• Droplet size distribution (Dv10, Dv50, Dv90): Indicators of the spread and median droplet size impacting deposition.
• Spray velocity: Influences droplet momentum and penetration into the oral cavity.
• Spray consistency between doses: Ensures minimal product variability across multiple actuations.

Key Properties and Parameters to Monitor During Validation

To successfully validate spray pattern and plume geometry, measurable parameters must be precisely monitored using suitable instrumentation:

• Imaging Systems: Use high-speed cameras or laser imaging to capture spray pattern shape and plume geometry.
• Laser Diffraction or Aerodynamic Particle Sizers: Measure droplet size distribution for assessing aerosol quality.
• Plume Angle Measurement Tools: Devices or software to quantify the angular spread of the spray plume.
• Flow rate and actuation force: Consistency in these parameters affects spray dynamics and must be controlled.
• Environmental Conditions: Temperature, humidity, and pressure should be monitored as they can influence spray characteristics.

Risk Assessment and Failure Mode Effects Analysis (FMEA) for Spray Pattern and Plume Geometry Validation

Begin by conducting a comprehensive Risk Assessment focused on critical quality attributes (CQAs) of the oral spray such as spray pattern uniformity and plume geometry consistency. Utilize a Failure Mode and Effects Analysis (FMEA) to systematically identify potential failure modes within the spray pattern and plume geometry validation process.

• Identify Failure Points: Potential issues include nozzle clogging, variation in actuator force, inconsistent valve performance, formulation viscosity changes, and equipment alignment errors.
• Severity Assignments: Assign severity based on the impact on product performance and patient safety. For example, poor plume geometry could result in insufficient dose delivery or deposition outside the oral cavity, impacting efficacy.
• Occurrence Evaluation: Estimate the likelihood of each failure mode based on historical data, equipment maintenance records, and formulation stability profiles.
• Detectability Consideration: Evaluate how easily the failure mode can be detected through in-process controls or testing methods.

Calculate Risk Priority Numbers (RPNs) by multiplying severity, occurrence, and detectability scores. Prioritize focus on failure modes with high RPN values for mitigation through control strategies and process parameters optimization.

Design of Experiment (DoE) for Critical Parameter Selection

Develop and implement a Design of Experiment (DoE) to systematically investigate the effects of critical process parameters (CPPs) on spray pattern and plume geometry characteristics.

1. Define CPPs: Typical CPPs include actuation force, actuator stroke length, valve opening pressure, nozzle orifice size, ambient conditions (temperature, humidity), and formulation viscosity.
2. Choose Experimental Design: Utilize factorial or fractional factorial designs to efficiently screen parameters and identify their main effects and interactions.
3. Set Response Variables: Measure spray pattern uniformity (e.g., diameter, circularity), plume angle, plume length, and spray deposition profile.
4. Conduct Experiments: Execute planned runs ensuring replicate samples to assess repeatability and robustness.
5. Analyze Results: Apply statistical tools (ANOVA, regression analysis) to determine significant parameters and define acceptable operating ranges.

Critical Process Parameters (CPP) Selection

Based on the DoE findings and risk assessment, pinpoint CPPs that directly influence spray pattern and plume geometry consistency. Examples may include:

• Actuation force and velocity
• Nozzle orifice diameter and geometry
• Valve spring tension
• Formulation viscosity and surface tension
• Ambient conditions at time of spray actuation

Establish parameter limits that maintain product quality within the validated acceptance criteria.

Control Strategy Development

Formulate a robust control strategy aimed at maintaining CPPs within defined limits throughout manufacturing.

• Equipment Calibration and Maintenance: Schedule regular calibration of actuators and verification of nozzle integrity.
• In-Process Monitoring: Implement real-time measurement of actuation force and valve pressure where feasible.
• Formulation Controls: Control viscosity and surface tension via raw material qualification and in-process testing.
• Environmental Controls: Maintain controlled temperature and humidity in manufacturing and testing areas.

Incorporate feedback loops to trigger corrective actions if parameters deviate from set limits.

Acceptance Criteria and Ranges

Establish acceptance criteria based on regulatory guidelines, scientific rationale, and clinical performance requirements to ensure consistent deposition and dosing.

• Spray Pattern Uniformity: Typically measured by the diameter of the sprayed area at a defined distance; acceptance range usually ±10% around the target diameter.
• Plume Angle: Defined angle range ensuring adequate dispersion within the oral cavity. For example, 30° to 60° depending on formulation and device design.
• Plume Geometry: Length, shape, and density assessed visually or via imaging software; criteria depend on product specifics.

All acceptance criteria must be justified based on functional performance and validated analytical methods.

Monitoring and Sampling Strategy

Define a systematic sampling and monitoring plan to verify ongoing process control and product consistency.

1. Sampling Points: Select critical points including initial batch qualification, during routine production, and post-maintenance validation.
2. Sample Size: Determine statistically valid sample numbers per batch based on process variability and batch size.
3. Frequency: For process performance qualification (PPQ), conduct comprehensive sampling of the entire batch. For routine monitoring, periodic sampling after successful validation.
4. Analytical Methods: Use validated imaging methods and software-based pattern analysis tools to measure spray pattern and plume geometry.

Process Flow and Stepwise Workflow for Validation Execution

Follow a structured workflow to ensure comprehensive and reproducible validation.

1. Pre-Validation Preparation: Verify equipment qualification completeness (IQ/OQ/PQ). Confirm calibration status and environment control.
2. Baseline Assessment: Collect initial baseline data on spray pattern and plume geometry using standard parameters.
3. DoE Implementation: Execute the designed experiments according to planned runs.
4. Data Analysis and Parameter Optimization: Analyze experimental data and refine CPP ranges.
5. Validation Batches Execution: Produce PPQ batches following optimized CPP setpoints and control strategies.
6. Sampling and Testing: Collect spray samples at defined intervals for pattern and plume geometry evaluation.
7. Data Review and Report Generation: Compile results, conduct statistical analysis, and confirm that acceptance criteria are met consistently.
8. Approval and Implementation: Upon successful validation, finalize control documents and incorporate validated parameters into manufacturing SOPs.

Protocol Design for Spray Pattern and Plume Geometry Validation

Design a detailed validation protocol encompassing all aspects of the process validation:

• Objective: Define purpose to establish and confirm spray pattern and plume geometry consistency.
• Scope: Specify product, equipment, and process parameters involved.
• Responsibilities: Assign roles for testing, data analysis, and decision-making.
• Materials and Equipment: List all instruments, software, and materials employed.
• Methodology: Detail sampling methods, DoE design, measurement techniques, and testing frequency.
• Acceptance Criteria: Clearly state limits for each measured attribute.
• Documentation and Reporting: Outline data recording, deviation handling, and final report requirements.

Process Performance Qualification (PPQ) Batch Execution and Evaluation

Execute multiple consecutive batches using the fixed CPP ranges derived from DoE studies to confirm process reproducibility and product quality.

1. Batch Setup: Confirm all equipment is cleaned, calibrated, and set to validated parameters.
2. Performance Monitoring: Record spray pattern and plume geometry parameters at predetermined intervals during batch runs.
3. Data Collection: Use validated analytical techniques for each sample to ensure accuracy and precision of measurements.
4. Statistical Evaluation: Compare results against acceptance criteria using appropriate statistical tests (e.g., control charts, capability indices).
5. Deviation Investigation: Promptly analyze any out-of-specification results with investigations and corrective actions.
6. Final Report: Summarize batch data, confirmation of validated parameters, approval status, and recommendations for routine monitoring.

Control Strategy Development for Spray Pattern and Plume Geometry

Based on DoE results and risk assessment findings, establish a robust control strategy to maintain CQAs within predefined limits during manufacturing.

• Critical Process Parameters (CPPs): Identify parameters with highest impact such as actuation force tolerance, valve opening pressure ranges, nozzle orifice dimensional control, and formulation viscosity limits.
• Control Measures: Implement equipment settings calibration, routine actuator performance checks, and validated formulation viscosity controls.
• In-Process Monitoring: Use in-line or at-line measurements such as high-speed camera imaging for plume geometry and spray pattern analyzers to ensure real-time conformance.
• Feedback Loops: Integrate automatic adjustment capability or manual intervention protocols if parameters drift beyond control limits.
• Documentation: Record control activities and outcomes adhering to GMP standards to support traceability and audit readiness.

Definition of Acceptable Ranges and Specifications

Define quantitative acceptance criteria for spray pattern and plume geometry based on clinical relevance and manufacturing capability:

• Spray Pattern Diameter: Maintain within ±10% of target diameter to ensure uniform dose coverage.
• Plume Angle: Set within a defined range (e.g., 40–60 degrees) to guarantee proper oral cavity deposition.
• Plume Length: Control maximal plume length to prevent aerosol escape outside intended area.
• Visual Consistency: Use image analysis to confirm circularity and absence of satellite droplets or droplets coalescence.
• Reproducibility: Ensure parameters fall consistently within limits across multiple batches and actuations.

Sampling Plan and Decision Points

Implement a rigorous sampling strategy during process performance qualification (PPQ) and routine manufacture:

• Sample Size: Extract multiple samples (e.g., 10 actuations per batch) from representative units to assess batch uniformity.
• Timing: Sample at defined time points including start, middle, and end of batch for stability over filling run.
• Decision Criteria: Apply statistical process control (SPC) rules; batches failing acceptance criteria require investigation and potential rejection or rework.
• Trend Analysis: Monitor ongoing data to detect process drifts or deviations early.

Process Performance Qualification (PPQ) Protocol Design

Develop the PPQ protocol to confirm consistent manufacturing capability within established control strategy:

• Scope: Define number of consecutive pilot or commercial scale batches (typically 3) for qualification.
• Parameters Monitored: CCP measurements including spray pattern dimensions, plume geometry metrics, actuator force, and valve pressure.
• Acceptance Criteria: Pre-established limits from development and DoE findings.
• Documentation: Detail test methods, sampling schedules, equipment calibration status, and data analysis approach.
• Change Control: Define actions for out-of-specification (OOS) results and protocol deviations.

PPQ Batch Execution and Evaluation

Conduct PPQ batches according to validated procedures to verify process robustness and product quality:

• Performance Monitoring: Record real-time data on spray pattern and plume geometry using validated instrumentation.
• Data Collection: Capture comprehensive datasets from all CCPs and quality checks for batch evaluation.
• Statistical Analysis: Evaluate consistency using control charts, capability indices, and variance analysis.
• Deviation Investigation: Document any anomalies, conduct root cause analysis, and apply corrective actions.
• Final Approval: Confirm acceptance of batch data and readiness for commercial production release.

Continuous Monitoring and Revalidation Triggers

Post-PPQ, establish ongoing monitoring systems to ensure transfer of validated state into routine manufacturing:

• Periodic Review: Assess historical data trends for spray pattern and plume geometry at set intervals.
• Change Management: Initiate revalidation upon changes in formulation, equipment, or process parameters impacting spray characteristics.
• Training: Maintain personnel competency on critical inspection techniques and control systems.
• Audit and Compliance: Schedule regular audits of control systems and process parameters documentation.

Introduction to Spray Pattern and Plume Geometry Validation in Oral Sprays Manufacturing

Spray pattern and plume geometry validation are critical components of process validation for oral spray dosage forms. Ensuring consistent spray characteristics directly impacts dose accuracy, therapeutic efficacy, and patient compliance. This validation step verifies that the spray actuator and formulation deliver a uniform spray pattern and plume geometry across production batches, meeting pre-defined acceptance criteria.

Before initiating spray pattern and plume geometry validation, verify that all related equipment (actuators, applicators, instrumentation) has undergone proper qualification (Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ)). This foundational qualification confirms the equipment is fit-for-purpose and performs consistently during the validation.

Define Acceptance Criteria and Validation Protocol

• Set quantitative acceptance criteria for spray pattern area and plume angle, typically based on pharmacopeial standards or product-specific requirements.
• Determine analytical methods and instrumentation to be used, such as high-speed videography, laser-based plume angle measurement devices, or digital image analysis software.
• Establish sample size for validation, commonly three consecutive production-scale batches.
• Define environmental and operational conditions for testing (temperature, humidity, nozzle actuation force).
• Develop a detailed validation protocol outlining responsibilities, procedures, data collection, and data analysis methods.

Conduct Spray Pattern Validation

1. Collect multiple sprays from each batch onto a suitable surface such as a glass plate or blotting paper for pattern visualization.
2. Use digital imaging or photographic techniques to capture the spray pattern clearly.
3. Measure spray pattern dimensions, including diameter and area, using validated image analysis software.
4. Repeat measurements for multiple sprays per batch (generally 10 actuations) to gather robust data.
5. Record all raw data and capture photographic evidence for traceability.

Perform Plume Geometry Validation

1. Trigger sprays in front of laser or high-speed cameras to capture the plume shape and angle.
2. Measure plume angle, height, and plume cone area using software calibrated to provide consistent outputs.
3. Perform measurements on multiple sprays per batch to ensure reproducibility and representativeness.
4. Document all data meticulously in controlled logbooks or electronic data capture systems.

Data Analysis and Tabulation of Results

Compile the measured data from the three validation batches into tabular format for clarity. Use the following table format:

Note: The Relative Standard Deviation (RSD) should be within established limits (e.g., <5%) to confirm consistency. Compliance is assigned based on whether results meet the predefined acceptance criteria.

Comparative Summary and Optimum Analysis

Prepare a comparative summary table to review results trend and assess batch-to-batch consistency:

Interpretation:

• The low RSD across batches suggests excellent reproducibility of the spray pattern and plume geometry.
• Compliance within acceptance limits confirms the process is robust and consistent across validated batches.
• Optimize parameters such as nozzle alignment or formulation viscosity if any out-of-specification results are observed during routine monitoring.

Continued Process Verification and Routine Monitoring

Following successful process validation, institute a program of continued process verification (CPV) to ensure ongoing control over spray pattern and plume geometry:

1. Set routine monitoring frequency (e.g., each production batch or defined intervals) for spray pattern and plume measurements.
2. Monitor and record all data systematically in batch manufacturing records.
3. Use trending charts and statistical tools to detect gradual process drifts or sudden deviations.
4. Investigate any outliers or deviations using root cause analysis and implement corrective actions where necessary.
5. Include spray pattern and plume geometry data in Annual Product Quality Review (APQR) and review trends annually.

Documentation and Annexure Templates

For comprehensive documentation, prepare the following annexures to be included in the validation master file:

• Annexure I: Spray Pattern Validation Raw Data Sheets – capturing all measurements, photos, and observations batch-wise.
• Annexure II: Plume Geometry Validation Raw Data Sheets – including instrument calibration logs and measurement readings.
• Annexure III: Validation Protocol Document – detailing the scope, methods, acceptance criteria, and responsibilities.
• Annexure IV: Validation Report Template – summarizing results, analysis, conclusions, and recommendations.
• Annexure V: Trending and CPV Log Template – for ongoing monitoring data collection and evaluation.

Ensure all annexures are signed and dated by responsible personnel and stored in a controlled quality system repository.

Conclusion

Validating spray pattern and plume geometry in oral spray manufacturing is essential to guaranteeing consistent product performance and patient safety. Through systematic execution of validation steps, rigorous data analysis, and establishment of robust routine monitoring, pharmaceutical professionals can maintain tight control over this critical process parameter. The use of structured documentation templates facilitates traceability and regulatory compliance, supporting a state of control for oral spray manufacturing operations.

Validation Result Tabulation and Analysis

Comparative Summary and Statistical Evaluation

Analysis: Relative Standard Deviation (RSD) values for both spray pattern and plume angle are well below the typical acceptance threshold of 5%, indicating high precision and reproducibility of the blowback and plume dimensions across batches.

Continued Process Verification (CPV) and Routine Monitoring

• Incorporate spray pattern and plume geometry measurements into routine in-process controls during manufacturing.
• Establish frequency and sampling plan for routine testing, e.g., every batch or every defined time period.
• Use control charts to monitor spray parameters and detect trends or shifts early.
• Investigate deviations or out-of-specification results per standard quality investigations.
• Document results and flag batches requiring further action or potential re-validation.

Annual Product Quality Review (APQR) and Trending

• Compile spray pattern and plume geometry data from routine monitoring for inclusion in APQR reports.
• Perform statistical trending analyses to evaluate process stability and detect subtle changes over time.
• Assess the impact of raw material variability, equipment wear, or environmental changes on spray characteristics.
• Recommend preventive maintenance or process adjustments based on trending outcomes.
• Review and update validation protocols or acceptance criteria as necessary in response to product lifecycle changes.

Annexures: Templates for Spray Pattern and Plume Geometry Validation

Annexure I: Spray Pattern Validation Data Collection Sheet

Batch No: ___________
Date: ___________
Operator: ___________

Spray No. | Spray Pattern Area (mm²) | Comments
----------|-------------------------|---------
1         |                         |
2         |                         |
...       |                         |
10        |                         |

Annexure II: Plume Geometry Measurement Sheet

Batch No: ___________
Date: ___________
Operator: ___________

Spray No. | Plume Angle (degrees) | Plume Height (mm) | Comments
----------|----------------------|------------------|---------
1         |                      |                  |
2         |                      |                  |
...       |                      |                  |
10        |                      |                  |

Annexure III: Spray Pattern and Plume Geometry Validation Summary Report Template

1. Objective:
2. Scope:
3. Equipment Used:
4. Acceptance Criteria:
5. Methodology:
6. Results Summary:
7. Statistical Analysis:
8. Conclusion:
9. Recommendations:

Annexure IV: Control Chart Template for Routine Monitoring

Parameter: __________________
Batch Number  | Measurement | Upper Control Limit | Lower Control Limit | Remarks
------------- | ----------- | ------------------- | ------------------- | --------
              |             |                     |                     |

Annexure V: Deviation and Investigation Log

Deviation ID: ___________
Date: ___________
Description:
Actions Taken:
Root Cause:
Corrective Actions:
Preventive Actions:
Follow-up Verification: