Dose Delivery Accuracy Validation in Oral Sprays Manufacturing: Key Quality Attributes and Validation Approach

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 and Impact on the Quality Target Product Profile (QTPP)

Accurate dose delivery directly influences critical QTPP attributes, ensuring that the oral spray delivers the intended therapeutic effect while maintaining patient safety and convenience. Key desired attributes include:

• Consistency and Precision: Each metered actuation must reliably deliver a dose within specification limits to maintain consistent drug bioavailability.
• Spray Characteristics: Uniform spray pattern and plume shape promote correct deposition and absorption in the oral cavity.
• Device Ergonomics: Actuation force and ease of use impact patient compliance and dosing accuracy.
• Stability Over Shelf Life: Dose delivery performance should remain unchanged throughout product stability duration.

These attributes synergistically impact the QTPP ensuring the product meets predefined clinical and regulatory requirements.

Identification of Critical Quality Attributes (CQAs) Related to Dose Delivery

Dose delivery accuracy validation targets specific CQAs that directly affect product performance and patient safety. These include:

• Dose Weight or Volume Accuracy: The weight/volume of formulation dispensed per actuation corresponding to label claim specifications.
• Dose Uniformity: Variability between actuations and across batches should remain within defined acceptable limits.
• Spray Pattern and Plume Geometry: Consistency in spray delivery ensures proper drug deposition and absorption.
• Actuation Force: The physical force required for spray activation influences dose delivery consistency and user acceptability.
• Device Priming and Repriming Behavior: Ensures reliable dose delivery after initial and subsequent uses.

Key Properties and Parameters to Measure During Validation

To robustly assess dose delivery accuracy, the following properties and parameters should be measured and documented during the validation protocol:

• Delivered Dose Content (mg or mL): Gravimetric or volumetric measurement of delivered dose per actuation over multiple cycles.
• Spray Pattern Assessment: Visual or instrument-based analysis (e.g., high-speed imaging) to evaluate plume geometry and coverage area.
• Particle Size Distribution (if applicable): For sprays containing particulate matter, measurement ensures consistent aerodynamic properties.
• Actuation Force Measurement: Instrumental quantification to verify ergonomic compliance and consistency.
• Priming/Repriming Dose Assessment: Ensures the first delivered doses meet specification following device storage or inactivity.

Collecting and analyzing data for these parameters provides a comprehensive picture of product performance relative to dose delivery.

Introduction to Dose Delivery Accuracy Validation in Oral Sprays Manufacturing

Validation of dose delivery accuracy in oral sprays manufacturing is critical to ensure consistent therapeutic efficacy, patient safety, and regulatory compliance. This validation confirms that the oral spray delivers the precise intended dose throughout the product lifecycle. All validation activities must integrate with prior equipment qualification (IQ/OQ/PQ), which ensures that the dispensing device and manufacturing equipment function within established specifications.

Risk Assessment and Failure Mode Effects Analysis (FMEA)

Begin the validation process with a detailed Risk Assessment and FMEA specific to dose delivery in oral sprays. This risk-based approach helps identify potential failure points, prioritize testing efforts, and establish controls.

• Identify critical quality attributes (CQAs): These typically include delivered dose volume, spray pattern, plume geometry, and droplet size distribution.
• Determine critical process parameters (CPPs): Such as actuation force, stroke length, spray nozzle dimensions, pump priming, and formulation viscosity.
• List potential failure modes: For example, inaccurate spray volume, clogging, inconsistent actuation, or device malfunction.
• Evaluate severity: Assess the impact of dose variation on safety and efficacy, usually rated on a 1–10 scale.
• Assess occurrence: Estimate the frequency of each failure mode, based on historical data and previous studies.
• Assess detectability: Determine how easily deviations can be detected with existing controls or testing methods.
• Calculate Risk Priority Number (RPN): Severity × Occurrence × Detectability guides prioritization of risk mitigation measures.

Design of Experiments (DoE) for CPP Selection

Utilize DoE methodologies to systematically explore the impact of CPPs on dose delivery accuracy. This step statistically confirms which variables most influence dosing performance.

• Define experimental factors (e.g., actuation speed, temperature, and pump priming cycles).
• Set factor ranges based on equipment and formulation specifications.
• Execute factorial or response surface designs to evaluate main effects and interactions.
• Measure delivered dose volume for each experimental run as the primary response.
• Analyze data to identify CPPs that significantly impact dose accuracy and precision.
• Establish acceptable operating ranges for these CPPs aligned with regulatory expectations.

Development of Control Strategy

After identifying CPPs, define a robust control strategy ensuring consistent dose delivery during routine manufacturing.

• In-process controls: Monitor actuation force, nozzle integrity, pump priming, and fill volume on the spray device.
• Process controls: Maintain formulation viscosity, environmental conditions (e.g., temperature, humidity), and device assembly checks.
• Sampling plan: Determine frequency and sample size for dose measurement during manufacturing runs to detect trends or deviations.
• Use validated analytical methods: For dose content uniformity and spray characterization tests, ensure all methods are sensitive, specific, and reproducible.

Defining Acceptable Ranges and Specifications

Set detailed acceptance criteria for dose delivery accuracy. Criteria should reflect clinical requirements and regulatory guidances.

• Establish nominal delivered dose and allowable variability, typically ±10% of target dose depending on label claims and pharmacopoeial standards.
• Set acceptance limits for spray pattern, plume geometry, and droplet size to ensure appropriate mucosal deposition.
• Define visual inspection criteria for nozzle clogging and leakage.
• Incorporate stability considerations to ensure dose accuracy throughout product’s shelf life.

Process Flow and Sampling Points

Outline the comprehensive process flow for dose delivery accuracy validation and identify key sampling points for data collection.

• Raw material preparation and batch compounding.
• Filling of formulation into spray device using precision pumps.
• Device assembly and priming verification.
• Dose delivery testing on finished units at predetermined intervals:
• Beginning of batch (BOB)
• Middle of batch (MOB)
• End of batch (EOB)
• Extended interval testing if batch size warrants.
• Environmental monitoring during batch execution to ensure consistent conditions.

Protocol Design for Process Performance Qualification (PPQ)

Develop a detailed PPQ protocol to document planned activities, acceptance criteria, and roles/responsibilities.

• Define scope including number of batches, batch sizes, and devices tested per batch.
• List all CPPs to be monitored and controlled during the qualification runs.
• Describe test methods for dose delivery accuracy, spray pattern, and other quality attributes.
• Specify sampling plan with rationales for sample sizes and points.
• Include acceptance criteria clearly consistent with prior steps.
• Outline data analysis procedures and decision rules for batch release.
• Identify contingency plans for out-of-specification results or process deviations.

Batch Execution and Data Evaluation

Perform PPQ batch manufacturing and execute sampling/testing per the protocol.

• Monitor CPPs continuously and record all process parameters during batch runs.
• Collect dose delivery samples as per sampling plan, ensuring representative coverage across batches.
• Perform analytical testing for delivered dose using validated chromatographic or gravimetric methods.
• Assess spray pattern and plume geometry using standardized visualization techniques.
• Document all non-conformances or unexpected events during manufacturing and testing.
• Compile data for trending and statistical analysis of dose variability.
• Confirm that all results meet acceptance criteria to qualify the process.
• If criteria are unmet, initiate root cause investigation and corrective action before subsequent batches.

Final Report and Continuous Monitoring

Prepare a comprehensive validation report summarizing findings, confirming process capability for dose delivery accuracy.

• Include summary tables, trends, and statistical analysis graphs.
• Document any deviations and their resolutions.
• Provide recommendations for ongoing process controls and monitoring during commercial manufacture.
• Establish periodic re-validation or verification schedules aligned with risk-based approaches.
• Leverage in-line or at-line dose measurement technologies, if feasible, for real-time monitoring as part of continuous improvement.

Control Strategy Development

Based on the Risk Assessment and DoE results, develop a robust control strategy to maintain dose delivery accuracy within predefined limits.

• Define acceptable ranges: Establish target specifications and acceptable tolerances for CQAs such as delivered dose volume (e.g., ±5% of label claim).
• Implement CPP controls: Set operational limits for actuation force, stroke length, nozzle dimensions, and other identified CPPs.
• In-process monitoring: Integrate real-time or at-line testing methods to monitor key attributes such as spray weight and pattern during manufacturing.
• Device inspection: Include routine checks for pump priming, nozzle cleanliness, and device functionality.

Process Flow and Stepwise Workflow Design

Develop a clear process flow outlining each manufacturing step critical to dose delivery accuracy:

1. Component inspection and verification (e.g., pumps, nozzles).
2. Formulation preparation and viscosity assessment.
3. Filling and device assembly with controlled parameters.
4. Pump priming and function check prior to batch commencement.
5. In-process dose delivery sampling at predefined intervals.
6. Final product inspection including dose delivery and spray performance tests.

Define sampling points at each stage to ensure early detection of deviations and minimize batch impact.

Sampling Plan and Decision Points

Implement a statistically sound sampling plan for dose delivery accuracy testing:

• Sample size selection based on batch size and criticality of the CQAs (for example, testing 10 units per batch initially).
• Decision criteria for batch acceptance or rejection, aligned with predefined dose accuracy limits.
• Include retesting provisions if initial samples fall outside acceptable ranges.
• Document all sampling results rigorously for trend analysis and continuous improvement.

Process Performance Qualification (PPQ) Protocol Design

Develop a comprehensive PPQ protocol to confirm that the oral spray manufacturing process consistently meets dose delivery specifications under routine production conditions.

• Objectives: Validate process capability and reproducibility for dose accuracy.
• Scope: Include all critical steps, including device assembly, priming, filling, and final testing.
• Execution plan: Specify number of batches (typically 3 consecutive), sampling methodology, and test methods.
• Acceptance criteria: Define quantitative dose volume limits and performance thresholds for each batch.
• Risk mitigation: Include contingency plans for investigation and corrective actions.

Batch Execution and Evaluation

Execute PPQ batches following the approved protocol with rigorous adherence to process parameters and sampling plans.

• Record and monitor all CPPs in real time, ensuring process adherence.
• Perform dose delivery measurements at all sampling points using validated analytical methods.
• Analyze batch data immediately to identify any deviations or trends.
• Compile a comprehensive summary report detailing batch performance against acceptance criteria.
• Implement corrective actions promptly if failures or trends toward non-compliance are detected.

Successful completion of PPQ confirms the oral spray manufacturing process reliably delivers accurate doses, complying with regulatory standards and ensuring patient safety.

Dose Delivery Accuracy 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.

Define Validation Objectives and Acceptance Criteria

Begin by clearly defining the objective of the dose delivery accuracy validation. The primary goal is to verify that the oral spray delivers the labeled dose consistently, accurately, and within predefined limits. Establish acceptance criteria based on pharmacopoeial standards, regulatory guidance, and product specifications, typically requiring dose uniformity within ±10% of the target dose with a Relative Standard Deviation (RSD) less than 5%.

Prepare Validation Protocol

Develop a comprehensive validation protocol that details the scope, methodology, sampling plan, analytical methods, equipment used, acceptance criteria, and documentation requirements. The protocol must include:

• Batch selection criteria (minimum three commercial-scale batches),
• Sampling procedures (number of actuations per batch),
• Analytical testing methods for active pharmaceutical ingredient (API) quantification,
• Defined acceptance limits for dose delivery accuracy,
• Responsibilities for execution, review, and approval.

Batch Selection and Sampling Plan

Select three representative commercial-scale batches manufactured under standard operating conditions and validated equipment settings. For each batch, sample dose delivery from multiple sites across the batch population (e.g., 10 units per batch, sampling from the start, middle, and end to ensure uniformity). Collect at least three repeated actuations per unit to measure consistency over usage.

Analytical Method Validation and Preparation

Confirm that the analytical method for determining API concentration in the delivered dose is fully validated for specificity, accuracy, precision, linearity, limit of detection, and quantitation. Prepare all necessary reagents, calibration standards, and controls prior to testing. Utilize instruments calibrated and qualified for analytical testing with traceable standards.

Perform Dose Delivery Accuracy Testing

Using the approved analytical technique, measure the API content for each collected sample. Document all raw data meticulously, ensuring batch number, sample ID, date, and analyst are recorded clearly. Calculate individual doses and average dose per batch, noting any deviation from the target dose.

Document and Tabulate Validation Results

Compile all data in a Validation Result Tabulation Table as shown below:

Repeat this tabulation for Batches 2 and 3 respectively.

Comparative Summary and Statistical Evaluation

Summarize dose delivery performance across batches in a Comparative Summary Table. Calculate batch averages, standard deviation, and RSD for each batch as follows:

Analyze the RSD values to confirm dose uniformity and control of manufacturing process variability. An RSD below 5% typically indicates optimal process performance and compliance with regulatory requirements.

Verification and Documentation for Continued Process Verification (CPV)

Establish a CPV plan to monitor dose delivery accuracy during routine manufacturing. This includes periodic sampling and testing of production batches, trend analysis of results, and documentation review as part of Annual Product Quality Review (APQR). Maintain detailed records of testing results and any deviations or corrective actions.

Routine Monitoring and Trending

Implement a schedule for regular dose delivery accuracy testing, incorporating process capability and stability studies. Use control charts and statistical tools to identify drifts or trends in dose delivery performance early, to enable timely process adjustments.

Review and Approval of Validation Documentation

Compile all validation data, protocols, raw results, statistical analyses, and CPV plans into a comprehensive validation report. Review this report through cross-functional teams including Quality Assurance, Production, and Analytical Development prior to final approval and filing.

Annexures Templates

Use the following templates as annexures to ensure comprehensive record-keeping and reproducibility:

• Annexure I: Dose Delivery Accuracy Validation Protocol Template
• Annexure II: Sampling Plan and Batch Selection Worksheet
• Annexure III: Analytical Method Validation Summary
• Annexure IV: Validation Result Tabulation Table Template
• Annexure V: Comparative Summary and Statistical Analysis Template

Each annexure should be completed, signed, and archived per your organization’s document control policies.

Validation Result Tabulation

Record and tabulate the dose delivery data obtained from testing each batch in a systematic manner. The table should include batch number, sample unit identification, individual dose results, mean dose, standard deviation, and Relative Standard Deviation (RSD) for each batch.

Comparative Summary and Statistical Analysis

Prepare a comparative summary table compiling mean dose, standard deviation, and RSD across the three batches to evaluate overall process consistency and compliance with acceptance criteria.

Calculate the overall RSD and confirm if it meets the predefined criteria (usually below 5%). Discuss any deviations and corrective actions if applicable.

Continuous Process Verification (CPV) and Routine Monitoring

Implement a CPV plan to monitor dose delivery accuracy during routine manufacturing post-validation. This plan should include:

• Regular sampling frequency (e.g., per production batch or at defined intervals)
• Sampling strategy consistent with validation sampling plan
• Documentation of test results with trending analysis over time
• Investigation and root cause analysis for any out-of-specification (OOS) results
• Periodic review meetings and statistical evaluation of trending data to ensure sustained process control

Annual Product Quality Review (APQR) and Trending

Incorporate dose delivery accuracy data in the APQR by including:

• Summary of validation and routine CPV results
• Statistical trending charts that highlight performance consistency and any variability patterns
• Evaluation of process capability indices as relevant
• Review of deviations, investigations, and any process improvements implemented
• Recommendations for ongoing control and potential further validation needs

Annexure I: Validation Protocol Template

(A structured document outlining scope, objectives, sampling, testing, acceptance criteria, responsibilities)

Annexure II: Sampling and Testing Record Template

(Log sheet to document sample identification, date/time, batch details, test results with signatures)

Annexure III: Analytical Method Validation Summary

(Documentation of method accuracy, precision, linearity, specificity, LOD/LOQ data)

Annexure IV: Validation Results Tabulation Template

(Blank tables structured as in Step 6 for organizing dose delivery data)

Annexure V: Comparative Summary and Trending Analysis Template

(Structured tables and charts for batch comparisons, RSD calculations, and CPV trending analysis)