Cleaning Validation Protocol and Standard Operating Procedure for Auto Coating Pan and Perforated Coating Pan in Oral Solid Dosage Manufacturing

Purpose and Scope

This document establishes the foundation for cleaning validation of the Auto Coating Pan and Perforated Coating Pan equipment used in the manufacturing of oral solid dosage forms. It defines the systematic approach and standard operating procedures (SOP) designed to ensure the removal of product residues, cleaning agents, and microbial contaminants to acceptable levels prior to changeover and start of subsequent manufacturing batches. This protocol is critical for ensuring product safety, efficacy, and compliance with regulatory requirements including cGMP guidelines.

The scope covers all process steps involving the coating pans, including product manufacturing, cleaning procedures, monitoring activities, and documentation. It is applicable to all products processed on these coating pans under this facility’s oral solid dosage manufacturing line.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

Personnel performing cleaning and validation activities must adhere strictly to safety protocols to prevent injury or exposure to hazardous materials. All personnel must wear appropriate PPE including but not limited to:

1. Safety goggles or face shield
2. Chemical-resistant gloves (compatible with cleaning agents used)
3. Long-sleeved lab coat or disposable coverall
4. Respiratory protection if handling volatile or dusty cleaning agents
5. Slip-resistant footwear

All cleaning agents and chemicals used must have associated Safety Data Sheets (SDS) accessible in the work area. Emergency wash stations and spill kits must be available and functional. Proper ventilation should be maintained in coating area during cleaning operations.

Equipment Overview and Product-Contact Parts

The Auto Coating Pan and Perforated Coating Pan are specialized equipment designed for applying pharmaceutical coatings to oral solid dosage forms. The principal components include:

* Product-contact parts require rigorous cleaning and validation to prevent cross-contamination.

Cleaning Strategy Overview

The cleaning strategy for the Auto Coating Pan and Perforated Coating Pan is designed to ensure effective removal of all residues, including coating formulations, powders, and cleaning agents. The approach involves:

1. Pre-Cleaning: Manual removal of gross product residues from accessible surfaces immediately after production completion using dedicated brushes and tools.
2. CIP (Clean-in-Place) or COP (Clean-out-of-Place): Use of automated spray rinse systems with validated detergent solutions where applicable. Hand-cleaning tools for parts not accessible by CIP.
3. Detergent Selection: Use of pharmaceutical grade detergent with proven efficacy against coating residues. Removal confirmed by TOC or specific analytical method.
4. Rinsing: Multiple rinses with purified water to remove detergent and soluble residues.
5. Drying: Adequate drying using air or heat to prevent microbial growth and residue re-aggregation.
6. Visual Inspection: Critical final check for physical cleanliness prior to sampling.
7. Sampling: Swab and rinse sampling of defined product-contact areas, leveraging validated sampling techniques.
8. Documentation & Review: All cleaning steps and sampling results documented in batch and validation records.

Cleaning Agents and Tools List

* Use controlled per site procedures and risk assessments.

Hold Times Definitions

Records and Forms List

Site-Specific Inputs Required

• Name and concentration of detergent: [detergent_name, concentration %]
• Validated rinse volume for each cleaning step: [rinse_volume_L]
• Maximum dirty hold time permitted: [max_dirty_hold_time_hours]
• Maximum clean hold time allowed before re-cleaning: [max_clean_hold_time_hours]
• Sampling surface area per swab location: [swab_area_cm2]
• Specific coating formulations and active pharmaceutical ingredients (API) processed (for residue risk assessment): [API_list]
• Analytical methods available for detergent residue confirmation (e.g., TOC, conductivity): [analytical_methods_available]
• Equipment layout diagram and cleaning access details

Auto Coating Pan / Perforated Coating Pan Cleaning Procedure

1. Pre-Cleaning Preparation
   1. Ensure the coating pan operation is complete and all product is discharged.
   2. Wear appropriate personal protective equipment (PPE) as per site safety norms.
   3. Remove any loose dust or bulk product residues inside the coating pan using a clean lint-free cloth or vacuum cleaner with a HEPA filter.
   4. Verify availability and freshness of [detergent_name], rinse water, cleaning tools, and appropriate containers for sample collection.
2. Disassembly
   1. Switch off and isolate the equipment from power supply as per lockout-tagout (LOTO) procedures.
   2. Disassemble easily removable parts such as pans, baffles, spray guns, chutes, and seals, following the equipment-specific dismantling SOP.
   3. Record part identification and location to ensure correct reassembly.
   4. Inspect disassembled parts visually for residual product or coating materials and place them on a clean surface or trays for individual cleaning.
3. Cleaning of Equipment Surfaces
   1. Prepare cleaning solution by diluting [detergent_name] as per manufacturer’s recommended concentration using purified water.
   2. Manually or mechanically clean disassembled parts with soft brushes and the detergent solution, ensuring all visible residues are removed.
   3. Clean fixed sections of the coating pan (main drum, perforated pan surfaces, chutes, and mounting framework) applying the detergent solution using lint-free cloths or spray methods as appropriate.
   4. Ensure detergent contact time of at least [contact_time_minutes] minutes to facilitate effective residue removal.
   5. Scrub all product contact surfaces thoroughly, paying particular attention to corners, perforations, and joints where residues can accumulate.
4. Rinsing Sequence
   1. Rinse all cleaned surfaces and disassembled parts with purified water at a minimum volume of [rinse_volume_L] liters or until no detergent foam or visible residue remains.
   2. Implement a final rinse with water of conductivity not exceeding [max_conductivity_µS/cm] to prevent introduction of contaminants.
   3. If detergent residue monitoring will be assessed by TOC or conductivity, collect rinse water samples post-rinsing as per sampling plan for analysis.
5. Drying
   1. Allow all parts and surfaces to air dry in a clean, dust-free environment or use clean compressed air (filtered, oil-free) for drying.
   2. Avoid use of cloths or materials that could reintroduce contaminants.
   3. Inspect visually for any moisture, particulates, or residue before reassembly.
6. Reassembly
   1. Reassemble the coating pan and associated parts strictly according to the equipment assembly SOP.
   2. Ensure all screws, fasteners, and seals are properly fixed to prevent ingress of contaminants during operation.
   3. Perform a functional check to confirm correct assembly and operation readiness.
7. Visual Inspection
   1. Conduct a thorough visual inspection of all product contact surfaces using appropriate light sources to detect any visible residues.
   2. Record inspection results in the cleaning batch record or logbook, noting any deviations or findings.
   3. If any visible residues are detected, repeat the cleaning and rinsing steps before proceeding to sampling.

Cleaning Process Parameter Table

Sampling Plan for Cleaning Validation

Sample Collection Methodology

1. Use validated swabbing technique with sterile cotton or polyester swabs moistened with [swab_solvent].
2. Swab the defined surface area by applying uniform pressure in a systematic pattern (e.g., vertical strokes, then horizontal strokes) covering the entire [swab_area_cm2].
3. Place swab in labeled sterile container immediately after sampling.
4. For rinse water, collect samples after the final rinse into appropriately labeled clean glass or polypropylene bottles.
5. Complete sample documentation form capturing time, date, sampler ID, equipment ID, location, and cleaning batch reference.
6. Transport samples to analytical laboratory with controlled temperature conditions (2-8°C) if delay exceeds 2 hours.
7. Maintain full sample chain-of-custody log from collection through receipt in laboratory.

Sampling Frequency and Timing

1. Perform sampling immediately after completion of cleaning and drying steps but prior to equipment reassembly.
2. Collect samples at each critical location during every validation run (minimum three consecutive runs recommended).
3. For routine cleaning verification, sampling frequency may be reduced as justified based on risk assessment and historical data.

Site-Specific Inputs Required

• Detergent name and concentration ([detergent_name], [detergent_concentration_%])
• Detergent contact time ([contact_time_minutes])
• Rinse water volume and quality ([rinse_volume_L], [max_conductivity_µS/cm])
• Swab area for each sampling location ([swab_area_cm2])
• Light intensity for visual inspection ([lux_value])
• Validated swabbing solvent ([swab_solvent])

Sampling Plan for Cleaning Validation

Sampling Locations

1. Swab critical contact points on the internal surface of the auto coating pan, including perforations, seams, and product contact zones.
2. Swab removable parts such as baffles, spray guns, chutes, and seals.
3. Collect rinse samples from the final rinse water drain or via swab-rinse procedures on fixed surfaces.

Sampling Methodology

1. Use validated, pre-moistened swabs designed for cleaning validation with a defined swab area of [swab_area_cm2].
2. Apply consistent pressure and swabbing pattern (vertical and horizontal strokes) on product contact surfaces to maximize residue recovery.
3. For rinse sampling, collect a defined volume ([rinse_sample_volume_mL]) of final rinse water immediately after completion of rinsing for analysis.
4. Label all samples clearly with equipment ID, location, date, time, and operator initials.
5. Transport samples under controlled conditions to the analytical laboratory promptly to prevent degradation.

Sampling Frequency

1. Perform initial cleaning validation sampling after the defined cleaning procedure has been executed following production of a high-risk or maximum carryover product.
2. For routine monitoring, conduct re-qualification sampling at defined intervals based on risk assessment (e.g., every 6 months or product change).
3. Additional sampling may be required in case of process deviations, cleaning failures, or equipment modifications.

Analytical Methods and Detection Limits

Chemical Residue Analysis

Microbial Monitoring (Risk-Based)

1. Assess microbiological contamination if product or cleaning agent is microbiologically sensitive or equipment design favors microbial harboring.
2. Use standard microbiological methods for aerobic plate count or bioburden testing with acceptance limits of [micro_limit_CFUs/cm2].
3. Include microbial sampling as defined by risk assessment protocols only.

Acceptance Criteria

PDE/ADE-Based MACO Limit Calculation

The Maximum Allowable Carryover (MACO) is calculated based on the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) limit of the previous product and dosage variables as follows:

1. Identify PDE/ADE value: [PDE_or_ADE_mg/day]
2. Determine maximum daily dose of the next product: [max_daily_dose_mg]
3. Calculate MACO per unit surface area (e.g., µg/cm²) considering the total surface area of the equipment: [equipment_surface_area_cm²]

MACO (µg/cm²) = (PDE or ADE × Safety Factor) / Equipment Surface Area

Safety factor is typically 10 to incorporate additional conservatism.

Residue levels below calculated MACO confirm acceptable cleaning efficacy.

Detergent Residue Limits

1. Detergent residues quantified by TOC or conductivity must not exceed [detergent_residue_limit_ppm], established via method validation and toxicological assessment.
2. These limits additionally ensure non-interference in subsequent manufacturing batches and product safety.

Fallback Legacy Acceptance Limits (If PDE/ADE Not Available)

Conduct validation using legacy approach for comparative purposes only:

• API residues not exceeding 10 ppm or 1/1000th of the lowest dose, whichever is more stringent.
• Detergent residues below site-specific limits validated by appropriate detection methods.

Documentation and Reporting

1. Document all cleaning validation activities including raw data, calculations, and deviations.
2. Compile comprehensive validation reports including sampling methods, analytical results, acceptance criteria comparisons, and conclusions.
3. Maintain traceability by linking batch records to validation documentation.
4. Report any non-conformances and corrective actions taken as part of continuous improvement.

Site-Specific Inputs Required

• [detergent_name]
• [rinse_volume_L]
• [contact_time_minutes]
• [max_conductivity_µS/cm]
• [swab_area_cm2]
• [LOD_API] – Limit of detection for API residues
• [LOD_TOC] – TOC detection limit
• [LOD_Conductivity] – Conductivity detection limit
• [micro_limit_CFUs/cm2]
• [PDE_or_ADE_mg/day]
• [max_daily_dose_mg]
• [equipment_surface_area_cm²]
• [detergent_residue_limit_ppm]
• [rinse_sample_volume_mL]

Recovery, Limit of Detection (LOD), and Limit of Quantitation (LOQ) Expectations

The validation of cleaning procedures for the auto coating pan and perforated coating pan must demonstrate reliable recovery, sensitivity, and quantitation capabilities of analytical methods used for residue detection. Recovery studies should be conducted by spiking known quantities of active pharmaceutical ingredients (API), excipients, and cleaning agents onto representative swab/sample surfaces mimicking actual equipment materials.

1. Recovery Expectations: A minimum recovery of 70–120% is typically accepted, ensuring method accuracy and robustness. This range verifies that the cleaning validation methods can reliably detect residues at concentrations relevant to acceptance criteria.
2. LOD and LOQ: Analytical methods for both API and detergent residues must demonstrate a Limit of Detection (LOD) and Limit of Quantitation (LOQ) sufficient to detect residues below established permissible limits derived from toxicological and regulatory considerations. Typically, LOQ values should be at or below the maximum allowable carryover levels calculated through PDE/ADE approaches.
3. Method Validation: Recovery, LOD, and LOQ parameters must be validated under worst-case conditions including relevant surfaces, small swab-sample areas (~[swab_area_cm2]), and in matrices containing potential interferences from formulation components or cleaning agents.

Acceptance Criteria Methodology

For the cleaning validation of auto coating pans and perforated coating pans used in oral solid dosage manufacturing, acceptance criteria shall be established primarily using the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE)-based Maximum Allowable Carryover (MACO) methodology. This approach ensures patient safety and compliance with international regulatory guidelines.

PDE/ADE-Based MACO Calculation

The PDE/ADE-based MACO is calculated as follows:

Using the above:

MACO (mg) = PDE_previous_API × BatchSize_next_product / Dose_next_product

The MACO represents the maximum allowable quantity of the previous product’s API residue allowable in the subsequent batch without compromising patient safety.

Establishing Cleaning Residue Limits

1. Calculate drug residue limit: The MACO value is converted into analytical residue limits by expressing the MACO per swabbed surface area or rinse volume:

Calculation	Description
Residue Limit (μg/cm²) = (MACO × 1,000,000) / Total Swabbed Surface Area (cm²)	Conversion from mg to micrograms divided by the validated swabbed area [swab_area_cm2]
Residue Limit (μg/mL) = (MACO × 1,000) / Rinse Volume (L)	Conversion for rinse sample results considering rinse volume [rinse_volume_L]

2. Analytical Method Sensitivity: Analytical methods must achieve an LOQ below the calculated residue limits to reliably detect and quantify residues at or below the MACO.
3. Fallback Legacy Limits: In case PDE/ADE data is not available, legacy approach limits such as ≤10 ppm or 1/1000th the normal product dose in residue may be used with full justification labeled as legacy and supported by risk assessment.

Detergent Residue Acceptance and Rationale

Residues from cleaning agents, such as detergents (e.g., [detergent_name]), must be evaluated for their removal post-cleaning due to potential toxicity, interference, or impact on product quality.

1. Analytical Method Selection: Detergent residues shall be monitored using suitable methods including Total Organic Carbon (TOC), conductivity, or detergent-specific assays (e.g., UV absorbance, surfactant-specific colorimetry), as applicable.
2. TOC Rationale: TOC provides a non-specific, sensitive measure of organic residues and is widely accepted in regulatory inspections. A TOC limit equivalent to or below the LOQ defined based on detergent use concentration and rinse volume shall be established.
3. Conductivity Rationale: Used when the detergent and its residues impact ionic conductivity. Limits shall be defined based on rinse water conductivity baselines post-cleaning.
4. Cleanup Justification: The detergent residue acceptance criteria must be justified by toxicity/risk assessment and the method’s sensitivity to ensure no adverse impact on subsequent product batches.

Handling Deviations and Corrective and Preventive Actions (CAPA)

Any deviations from the validated cleaning procedure, analytical method acceptance criteria, or unexpected residue levels identified during routine cleaning verification shall trigger an investigation and, if applicable, CAPA implementation:

1. Deviation Reporting: All cleaning validation deviations must be documented with full root cause analysis.
2. Assessment of Impact: Evaluate the impact on product safety, quality, and regulatory compliance.
3. Corrective Actions: Actions may include additional cleaning cycles, equipment redesign, enhanced training, or updated cleaning agents/protocols.
4. Preventive Actions: Prevent recurrence through update of cleaning SOPs, process controls, or improved monitoring strategies.
5. Revalidation: Where deviation suggests process failure or procedural changes, partial or full revalidation must be performed per revalidation triggers outlined below.

Continued Verification Plan

To maintain cleaning validation status post-approval, a continued verification program must be implemented incorporating routine monitoring consistent with site-specific risk assessment:

1. Routine Sampling: Following the Sampling Plan defined in Part B, periodic monitoring of equipment surfaces and rinses shall be performed to verify residue control over time.
2. Trend Analysis: Residue levels shall be trended and statistically evaluated to detect any early signs of cleaning performance degradation.
3. Frequency: The frequency of monitoring may decrease after demonstrating sustained control but must be sufficient to detect variability, with frequency site-specific (e.g., quarterly, bi-annually).
4. Response Threshold: Rising trends or detections above acceptance criteria shall trigger investigation and CAPA.

Revalidation Triggers

The following scenarios require revalidation of the cleaning process for auto coating pans/perforated coating pans:

Annexures and Templates

The following annexures and templates shall support execution, record keeping, and compliance for the cleaning validation protocol and cleaning procedure:

Site-specific inputs required:

• [detergent_name]
• [rinse_volume_L]
• [swab_area_cm2]
• [PDE_previous_API_mg/day]
• [BatchSize_next_product_units]
• [Dose_next_product_mg]

Conclusion

The cleaning validation program for the auto coating pan and perforated coating pan outlined herein aligns with global regulatory expectations by applying PDE/ADE-based MACO methodology to define scientifically justified acceptance criteria. Analytical methods included within this protocol meet rigorous performance characteristics for recovery, LOD, and LOQ, ensuring confidence in residue detection and quantitation. The incorporation of detergent residue evaluation acknowledges the potential risk of cleaning agent carryover and ensures patient safety is uncompromised. Deviation management, continued verification, and clear revalidation triggers form a robust governance framework supporting ongoing compliance and product quality. By adhering strictly to this protocol and the associated SOP-style cleaning procedure referenced in Part B, pharmaceutical manufacturing sites can reliably achieve validated cleaning processes that safeguard product purity and regulatory compliance.