Cleaning Validation Protocol and Procedure for Nasal Spray Filling Machine Product Contact Components

Purpose and Scope

This document establishes a standardized cleaning validation protocol and provides an SOP-style cleaning procedure specifically for the product-contact parts of nasal spray filling machines used in pharmaceutical manufacturing. The primary objective is to confirm that the cleaning process effectively removes residues of active pharmaceutical ingredients (API), excipients, detergents, and microbial contaminants to pre-defined acceptable levels, supporting product quality, patient safety, and regulatory compliance.

This protocol applies to all nasal spray filling equipment utilized in the production of nasal dosage forms within the manufacturing facility. It encompasses cleaning process development, validation, and routine monitoring phases, ensuring reproducible cleanliness of all product-contact surfaces prior to subsequent product batches or changes in product lines. The scope excludes non-product-contact parts and general facility cleaning procedures unless specified.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

All personnel involved in the cleaning and validation activities must adhere strictly to safety guidelines to minimize exposure to hazardous chemicals and physical risks. The following PPE must be worn at all times during the cleaning process involving product-contact parts of the nasal spray filling machine:

• Chemical-resistant gloves (e.g., nitrile gloves resistant to cleaning detergents)
• Protective goggles or face shields
• Laboratory coats or chemical-resistant gowns
• Respiratory protection if required by material safety data sheets (MSDS) of detergents or solvents
• Closed-toe, slip-resistant shoes
• Hair nets or caps to prevent contamination

Safety data sheets (SDS) for all detergents and cleaning agents used must be accessible at the cleaning site. Emergency eye wash stations and safety showers must be functional and known to operators. Proper ventilation must be ensured during cleaning activities involving volatile substances.

Equipment Overview and Product-Contact Parts Description

The nasal spray filling machine utilized within this protocol is designed for aseptic and accurate volumetric fill of nasal spray formulations into pre-sterilized containers. The following product-contact parts have been identified based on direct contact with formulation or components exposed to product residues and thus subject to cleaning:

All product-contact surfaces are designed for Clean-in-Place (CIP) or manual cleaning, depending on the component accessibility. Surface finishes are documented, with electrical conductivity and roughness measurements to support cleaning validation risk assessments.

Cleaning Strategy Overview

This cleaning validation protocol adopts a risk-based, science-driven approach to ensure effective removal of residues from all product-contact parts, prioritizing prevention of cross-contamination and residual accumulation. The cleaning strategy is segmented as follows:

• Cleaning Method Type: Manual cleaning for accessible parts; CIP utilizing automated detergent and rinse cycles for internal passages and manifolds.
• Detergent Selection: Use of pharmaceutical-grade, validated neutral or alkaline detergents compatible with equipment materials to efficiently remove protein, API, and particulate residues.
• Cleaning Sequence: Pre-rinse (water) → Detergent wash → Intermediate rinse (water) → Final rinse (purified water or WFI as applicable) → Drying (air or heat drying methods).
• Cleaning Frequency: After each product campaign or batch changeover, with hold time restrictions on dirty parts.
• Critical Process Parameters (CPPs): Detergent temperature, contact time, flow rates during CIP, and mechanical action on manual cleaning parts.
• Residue Monitoring: Visual inspection, TOC, and swab sampling for API and detergent residues supported by validated analytical methods.
• Microbial Considerations: Cleaning to reduce bioburden on product-contact surfaces to levels compatible with GMP for nasal dosage forms.

Cleaning Agents and Tools List

Hold Time Definitions

Records and Forms List

• Cleaning Procedure Log Sheet – Documentation of cleaning operations including date, time, operator, detergents, volumes, and temperature.
• Cleaning Verification Sampling Forms – Records of swab and rinse samples collected from product-contact surfaces.
• Analytical Results Report – Compilation of laboratory testing results for API, detergent residues, and microbial counts, if applicable.
• Cleaning Validation Protocol Approval Sheet – Document sign-off and approvals.
• Deviation and Incident Report Forms – For documenting unexpected events or non-conformances during cleaning validation.
• Equipment Maintenance and Calibration Logs – Records ensuring equipment used in cleaning and sampling is maintained per GMP requirements.
• PPE Compliance Checklist – Documentation confirming proper PPE usage by personnel.

Site-specific Inputs Required

• Exact detergent product name and concentration: [detergent_name]
• Detergent dosage and rinse volume parameters: [detergent_concentration], [rinse_volume_L]
• Hold times for dirty and cleaned equipment states: [dirty_hold_time_hours], [clean_hold_time_hours]
• Sampling surface area for swab and rinse samples: [swab_area_cm2], [rinse_sample_volume]
• Detergent residue limit specification methodology: TOC, conductivity or specific assay method specifics
• Maximum allowable residual limits based on site toxicological risk assessments: PDE/ADE values for APIs and detergents
• Environmental conditions for cleaning and drying: temperature, humidity controls
• Equipment model and configuration validation details: serial numbers, component drawings

Cleaning Procedure for Nasal Spray Filling Machine (Product Contact Parts)

1. Pre-Cleaning Preparation
   1. Wear appropriate personal protective equipment (PPE) including gloves, goggles, and aprons.
   2. Prepare cleaning area ensuring all required cleaning materials and tools are available: [detergent_name], brushes, lint-free cloths, swabs, rinse water, and drying equipment.
   3. Ensure the machine is shut down and disconnected from power before cleaning begins.
   4. Log the cleaning start time, personnel performing the cleaning, and batch reference in the cleaning logbook.
2. Disassembly
   1. Remove all product contact parts from the nasal spray filling machine according to the manufacturer’s disassembly instructions.
   2. Place disassembled parts on a clean, validated surface or tray labeled with the batch and equipment ID.
   3. Inspect disassembled parts visually for any physical defects or residue buildup before commencing wash.
3. Cleaning (Wash) Step
   1. Prepare the cleaning solution using [detergent_name] at the concentration specified in the detergent manufacturer’s instructions.
   2. Use warm water at a temperature of [wash_temperature_°C] ± 5°C to prepare the cleaning solution.
   3. Immerse product contact parts fully into the detergent solution or apply detergent solution thoroughly using a compatible brush.
   4. Agitate parts in the solution or scrub manually for a minimum of [wash_time_minutes] minutes, ensuring mechanical action to dislodge residues.
   5. Rinse brushes and cleaning tools in detergent solution between uses to avoid cross-contamination.
   6. Discard detergent solution after use or as per validated discard criteria.
4. Rinse Steps
   1. Conduct a primary rinse using purified water at a volume of [rinse_volume_L] per part or assembly.
   2. Rinse parts individually to ensure the complete removal of detergent residues.
   3. Perform a secondary rinse with purified water or water for injection (WFI), depending on product compatibility and site standards.
   4. Monitor rinse water conductivity or TOC level to verify detergent removal during the rinse phase.
   5. Repeat rinse steps if required until rinse water meets predefined acceptance criteria.
5. Drying
   1. Dry cleaned parts using lint-free cloths or filtered compressed air to remove residual moisture.
   2. Ensure drying is performed in a clean, controlled environment to prevent recontamination.
   3. Confirm visually that all parts are free from water spots and have completely dried before reassembly.
6. Reassembly
   1. Reassemble the cleaned and dried product contact parts as per the equipment manual.
   2. Confirm that all parts have been correctly assembled and securely fastened.
   3. Record reassembly completion time, personnel involved, and any observations in the cleaning log.
7. Visual Inspection
   1. Perform a thorough visual inspection of the reassembled filling machine product contact parts under appropriate lighting conditions.
   2. Look for any visible residues, stains, discoloration, or mechanical damage.
   3. Document findings and approve equipment readiness for sampling.
   4. If visual cleanliness is not confirmed, repeat the cleaning process.

Cleaning Parameters Table

Sampling Plan for Cleaning Verification

Additional Sampling Plan Details

1. Site-Specific Input Requirements:
   • [detergent_name]
   • [swab_solution] (e.g., purified water, buffer)
   • [swab_area_cm2]
   • [storage_temperature]
   • [flush_volume_mL] if flush sampling applied
   • [environment_class]
2. Sample Collection and Handling Procedure:
   1. Use aseptic techniques during swab sampling to prevent contamination.
   2. Seal swabs immediately in sterile sample containers or bags post-sampling.
   3. Document chain-of-custody including sampler name, time, and sample transfer details.
   4. Transport samples under conditions preventing degradation of residues/detergents.
   5. Submit samples to the Quality Control laboratory within [timeframe_hours] post-collection.
3. Sampling Frequency:
   • Routine cleaning validation: Minimum 3 consecutive batches.
   • Post-maintenance or process change: re-validation sampling required.
   • Periodic re-validation: annually or as per site-specific risk assessments.
4. Sampling Tools and Materials:
   • Sterile swabs validated for recovery efficiency.
   • Sterile sample transport containers.
   • Labels and chain-of-custody forms compliant with GMP documentation standards.

Verification of Cleaning Effectiveness

Visual Inspection

1. Inspect all cleaned product contact parts under adequate lighting conditions for any visible residues, discoloration, or damage.
2. Document visual observations on the cleaning log with photographs if necessary.
3. If residues or damage are detected, repeat cleaning procedures before proceeding to sampling.

Analytical Sampling

1. Identify sampling locations based on risk assessment and contact surface area of each part.
2. Using sterile swabs moistened with validated solvent, sample an area of [swab_area_cm2] cm² per location according to the sampling plan defined in Part B.
3. Collect duplicate samples for method validation and confirmatory analysis.
4. Label and securely transport samples to the QC laboratory for analysis.

Microbiological Considerations (Risk-Based)

1. Assess the risk of microbial contamination based on product characteristics and processing environment.
2. If applicable, conduct microbiological sampling on critical surfaces using contact plates or swabs.
3. Establish acceptance limits based on historical data and regulatory guidance. Document these limits explicitly.
4. Perform microbial enumeration and identification according to established microbiology SOPs.

Cleaning Validation Acceptance Criteria

Residue Acceptance Limits – PDE/ADE-based MACO Methodology

The Maximum Allowable Carryover (MACO) is calculated to establish residue limits using the following formula:

MACO (mg) = (ADE × BatchSize) / Safety Factor

The acceptable residue limit per unit area or part surface is set to ensure that potential cross-contamination does not exceed the MACO value relative to the next product dose.

Legacy Residue Limits (Fallback Approach)

Where PDE/ADE data are unavailable, legacy acceptance limits may apply:

• Residue ≤ 10 ppm of the next product dose
• Or ≤ 1/1000 of the smallest therapeutic dose of the next product batch

Legacy criteria shall be clearly marked as fallback and justified accordingly.

Detergent Residue Limits

1. Residual detergent levels will be monitored using [analytical_method_name] (e.g., TOC, conductivity, specific detergent assay).
2. Acceptance criterion: Detergent residue concentration ≤ [detergent_residue_limit] mg/cm² or equivalent parameter linked to method sensitivity.
3. Justification of limits based on method detection limit and safety/toxicity data for detergent components.

Microbial Limits (If Applicable)

1. Maximum total aerobic microbial count should not exceed [microbial_limit_cfucount] CFU/cm² or per sample.
2. Pathogenic organisms (e.g., S. aureus, P. aeruginosa) must be absent in 25 cm² areas or equivalent sample volume.
3. Limits are validated based on historical data and risk assessment.

Documentation and Records

1. Complete and sign the cleaning log sheet, including start/end times, personnel, cleaning agents and lot numbers.
2. Record disassembly and reassembly checks.
3. Attach sampling logs and laboratory analysis reports.
4. Document any deviations or corrective actions encountered during cleaning or validation.
5. Maintain records for a minimum period as per regulatory and site requirements.

Site-Specific Inputs Required

• [detergent_name]: Name and concentration details of the cleaning agent.
• [wash_temperature_°C]: Target wash temperature ± acceptable variance.
• [wash_time_minutes]: Minimum scrub/immersion time for cleaning.
• [rinse_volume_L]: Volume of purified water for rinsing per part.
• [swab_area_cm2]: Surface area for analytical swabbing at each location.
• [ADE_mg/day]: Acceptable Daily Exposure value for product residues.
• [MDP_mg]: Maximum daily dose of the next product after equipment cleaning.
• [BatchSize_n_units]: Next product batch size in the same equipment.
• [detergent_residue_limit]: Maximum acceptable detergent residue limit based on analytical method.
• [analytical_method_name]: Method used for detergent residue determination.
• [microbial_limit_cfucount]: Acceptable microbial count limit where applicable.

Analytical Method Performance and Validation

The analytical methods used to detect residues on the nasal spray filling machine product contact parts must demonstrate adequate sensitivity, specificity, accuracy, and precision to ensure reliable cleaning validation results. Key analytical performance parameters include recovery, limit of detection (LOD), and limit of quantitation (LOQ).

Recovery Expectations

Recovery studies shall be conducted by spiking known concentrations of the product residues and cleaning agents onto representative product contact surfaces. These spiked surfaces will then undergo the sampling and analytical procedure to verify the percentage of residue recovered through the entire workflow. Acceptance criteria for recovery are as follows:

1. Product Residue Recovery: ≥ 70% recovery across relevant concentration ranges to ensure the method can accurately capture residual active pharmaceutical ingredients (APIs) and excipients.
2. Detergent Recovery: ≥ 80% recovery to confirm reliable measurement of detergent residues via the selected analytical technique.

Failure to meet these recovery thresholds must prompt re-optimization of sampling protocols or analytical methods until acceptable performance is achieved.

Limit of Detection and Limit of Quantitation

Analytical methods must demonstrate the capability to detect and reliably quantify residues at levels below the established acceptance criteria. Expected LOD and LOQ should be determined experimentally during method validation and reported in the study documentation. Typically:

1. LOD: The lowest concentration detectable but not necessarily quantifiable, generally corresponding to a signal-to-noise ratio (S/N) of 3:1.
2. LOQ: The lowest concentration quantitatively measurable with acceptable accuracy and precision, typically corresponding to an S/N of 10:1.

LOD and LOQ values must be sufficiently low to detect residues at or below the Maximum Allowable Carryover (MACO) concentration defined in the acceptance criteria section.

Acceptance Criteria Methodology

PDE/ADE-Based MACO Framework

The primary approach for establishing acceptance criteria for residual product on the nasal spray filling machine is based on the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) concept, using the Maximum Allowable Carryover (MACO) methodology. This approach ensures patient safety by limiting cross-contamination risks to below clinically relevant thresholds derived from toxicological evaluations.

The MACO calculation framework requires the following key site-specific inputs:

• PDE or ADE for the API (mg/day)
• Batch size of the subsequent product manufactured on the same equipment (kg or number of units)
• Maximum daily dose of the subsequent product (mg/day)
• Maximum acceptable dose of the previous product allowed to cross-contaminate (usually set conservatively in relation to PDE/ADE)

MACO Calculation Structure (Example):

The cleaning validation acceptance level for residue is then set at or below this MACO value to ensure patient safety and regulatory compliance. MACO values must be adjusted for specific toxicological endpoints or local regulatory requirements where applicable.

Legacy Acceptance Limits (Fallback)

In the absence of PDE/ADE values or specific toxicological data, legacy acceptance limits may be considered as a fallback approach. These include:

• Not exceeding 10 ppm residual product on cleaned surfaces
• Residue concentration less than one-thousandth (1/1000) of the minimum therapeutic dose

Note: These legacy limits are superseded by the PDE/ADE MACO approach wherever toxicological data are available and shall only be utilized when such data are unavailable.

Detergent Residue Acceptance Rationale

Cleaning agents or detergents used in the cleaning process must also be controlled to prevent carryover into subsequent batches. Residual detergent acceptance criteria shall be based on specific analytical methods such as Total Organic Carbon (TOC) analysis, conductivity measurements, or dedicated detergent-specific assays (e.g., HPLC or colorimetric methods). The selection and justification of the method must align with the detergent’s chemical nature and the lowest detectable concentration relevant to safety risk assessments.

Key considerations for detergent residue limits include:

1. Analytical Sensitivity: The method must have LOQ lower than the established residual detergent limit.
2. Biocompatibility and Toxicology: Residual detergent limits are defined based on toxicological safety margins or pharmacopoeial guidelines (if available).
3. Method Accuracy and Robustness: The method must be validated with acceptable precision and recovery on representative surfaces.

Typically, detergent residue acceptance is set based on validated TOC limits of less than [detergent_limit_ppm] ppm or detergent-specific limits according to toxicological data.

Deviations and Corrective and Preventive Actions (CAPA)

Any deviations observed during cleaning validation execution, sampling, or analytical testing must be comprehensively documented and investigated according to site deviation management procedures. Potential deviations include:

• Failure to meet recovery criteria for analytical methods
• Residue levels exceeding acceptance criteria
• Sampling or cleaning procedure non-compliance
• Analytical method out-of-specification or inconsistencies

Corrective and Preventive Actions (CAPA) to address identified deviations might involve:

1. Re-training of personnel on procedures and sampling techniques
2. Re-validation or re-qualification of analytical methods
3. Optimization or revision of cleaning methods and parameters
4. Additional sampling and analysis to confirm root cause resolution

CAPA implementation must be documented with efficacy checks embedded to prevent recurrence and ensure ongoing process robustness.

Continued Verification and Revalidation Plan

Once cleaning validation is successfully completed and acceptance criteria are met, it is mandatory to implement a formal continued verification plan to ensure consistent cleaning effectiveness during routine manufacturing. This plan should include:

• Periodic sampling and analysis of cleaned equipment surfaces according to a defined schedule (e.g., quarterly, biannually)
• Review of cleaning batch records for process deviations
• Monitoring trends in cleaning residue data to detect potential drift
• Validation of any changes in product formulations, equipment, cleaning agents, or process parameters that could impact cleaning effectiveness

Revalidation triggers shall include but are not limited to:

1. Introduction of new products or APIs with different toxicological profiles
2. Significant equipment modifications impacting product contact surfaces
3. Changes in cleaning agents, detergents, or procedures
4. Deviations or failures in routine verification sampling
5. Regulatory inspections recommending revalidation or process improvements

Revalidation activities will encompass repetition of cleaning runs, resampling per validated plans, and re-analyses with updated validation documentation.

Annexures and Templates

The following annexures and templates shall be part of the cleaning validation documentation package to support reproducibility and compliance:

Conclusion

The cleaning validation of the nasal spray filling machine product contact parts is essential to guarantee product safety, quality, and regulatory compliance by minimizing cross-contamination risks. This document establishes the justification and governance framework by defining robust analytical acceptance criteria based primarily on PDE/ADE-derived MACO limits, supported by validated sensitive methods that demonstrate adequate recovery, LOD, and LOQ. A risk-based approach governs detergent residue acceptance with appropriate analytical rationale. Any deviations identified during validation are addressed through comprehensive CAPA to maintain process integrity. Continued verification and revalidation plans outlined herein provide structured oversight to assure sustained cleaning efficacy throughout the equipment lifecycle. Annexures and templates supplied facilitate standardized execution, documentation, and audit readiness of the cleaning validation program.