Cleaning Validation Protocol and Procedures for Capsule Polishing Machine Product Contact Parts

Purpose and Scope

The purpose of this document is to establish a robust, inspection-ready cleaning validation protocol specifically focused on the product contact parts of the capsule polishing machine used in the manufacturing of oral solid dosage forms. This protocol aims to ensure the effective removal of residues, preventing cross-contamination and guaranteeing patient safety by validating that cleaning procedures meet predefined acceptance criteria.

The scope covers the cleaning validation lifecycle including detailed cleaning strategies, definitions, responsibilities, equipment overview, safety precautions, and documentation required prior to analytical acceptance criteria and sampling plans. It pertains exclusively to product contact parts of capsule polishing machines within cGMP-compliant pharmaceutical manufacturing environments.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

Personnel involved in cleaning and validation activities must follow all applicable safety regulations pertinent to chemical handling, cleaning agents, and equipment operation. The following PPE must be worn as a minimum during cleaning and sampling:

1. Laboratory coat or disposable gown resistant to chemicals
2. Chemical-resistant gloves (type matched to detergent used, e.g. nitrile or neoprene)
3. Safety goggles or face shield for eye protection
4. Respiratory protection if volatile chemicals or aerosols are generated
5. Closed-toe, slip-resistant footwear
6. Hair net and beard covers, if applicable

Additional site-specific PPE requirements may be mandated based on risk assessments and localized safety protocols.

Equipment Overview and Product Contact Parts

The capsule polishing machine is an integral piece of oral solid dosage production equipment designed to remove excess dust and debris from soft or hard gelatin capsules, improving product quality and appearance. Only the product contact surfaces are validated under this cleaning protocol, encompassing:

• Rotating polishing drum or barrel liner
• Product feed chute and product outlet chute
• Internal baffling and polishing brushes
• Feed screws or auger, if applicable
• Cleaning nozzles or spray systems dedicated to product contact parts
• Any detachable covers or lids contacting product

Non-product contact external surfaces are cleaned per routine GMP hygiene SOPs, and not part of this validation.

The machine construction typically includes stainless steel (316L or equivalent), food-grade plastics, and polymer seals; surface finish and design features should support cleanability with minimal risk of residue entrapment.

Cleaning Strategy Overview

This cleaning validation protocol utilizes a science and risk-based approach to demonstrate residue removal, combining mechanical action, appropriate detergents, and rinsing steps. The high-level cleaning strategy includes:

1. Pre-Cleaning: Bulk product removal by vacuum, brush, or blow-down to prevent buildup.
2. Cleaning Agent Application: Circulation or manual application of [detergent_name] formulated to dissolve product residues and associated dust.
3. Detergent Hold Time: Allow sufficient contact time for effective residue dissolution, typically [detergent_hold_time_minutes] minutes.
4. Rinse Procedure: Multiple rinses with purified water or [rinse_solution], volume of at least [rinse_volume_L] liters per rinse, until residue and detergent are cleared.
5. Final Rinse Validation: Analytical monitoring of rinse water and swab samples from critical points for residual drug substance, cleaning agent, and microbiological indicators as applicable.
6. Drying: Proper drying or air blow-off to prevent microbial growth and enable visual inspection.

The cleaning cycle frequency aligns with defined maximum dirty hold times to prevent residue hardening or microbial proliferation.

Cleaning Agents and Tools List

Hold Time Definitions

Records and Forms List

Proper documentation is essential for compliance and traceability throughout the cleaning validation lifecycle. The following records and forms must be generated, completed, and retained in alignment with site document control procedures:

• Cleaning Validation Protocol Document
• Cleaning Procedure (SOP) for Capsule Polishing Machine
• Cleaning Batch Records capturing cleaning cycle parameters and operator details
• Sampling Forms for swab and rinse sample collection with defined locations
• Analytical Test Results Reports for residue assays and detergent residue monitoring
• Equipment Cleaning Logs for routine cleaning outside validation campaigns
• Deviation and Corrective Action Reports should any cleaning deviations arise
• Final Cleaning Validation Report summarizing acceptance criteria and study conclusions

Site-Specific Inputs Required

• [detergent_name] – Name, formulation, concentration, supplier details
• [rinse_volume_L] – Volume of water per rinse cycle optimized for equipment size
• [detergent_hold_time_minutes] – Contact time for detergent on product contact parts
• [dirty_hold_time_hours] – Maximum dirty hold time allowed post-production
• [clean_hold_time_hours] – Maximum clean hold time allowable post-cleaning before sampling/use
• [swab_area_cm2] – Defined swabbing surface area for residue sampling depending on component size
• [analytical_methods] – Specific assay methodologies used for drug, detergent, and microbiological residue detection (e.g., HPLC, TOC, conductivity)
• [equipment_part_descriptions] – Detailed nomenclature of product contact parts unique to the capsule polisher model
• [sampling_locations_map] – Site-specific diagram or description of swab and rinse sample points
• PPE requirements beyond standard, if applicable by site risk assessment
• Environmental and utility specifics that may influence rinse water quality or cleaning agent compatibility

Capsule Polishing Machine Cleaning Procedure (Product Contact Parts)

1. Pre-Cleaning Preparation
   1. Ensure capsule polishing machine is stopped and locked out according to site safety protocols.
   2. Remove all loose product residues by vacuuming or brushing the exterior surfaces with a clean, dry brush.
   3. Wear appropriate personal protective equipment (PPE) including gloves, goggles, and protective garments.
2. Disassembly of Product Contact Parts
   1. Disassemble all product contact parts as per the equipment-specific SOP:
   1. Remove polishing brushes, chutes, and sieves following manufacturer’s instructions.
   2. Disconnect and remove feed hoppers and any detachable covers or panels contacting product.
   2. Place removed parts on a clean, sanitized surface designated for cleaning parts.
3. Manual Washing of Product Contact Parts
   1. Prepare cleaning solution at specified concentration using [detergent_name].
   2. Immerse product contact parts fully in cleaning solution tanks and allow to soak for [soak_time_minutes].
   3. Use soft brushes or non-abrasive cloths to scrub all surfaces thoroughly, targeting crevices and hard-to-reach areas.
   4. Refresh cleaning solution if visibly contaminated or after cleaning each batch of parts.
   5. Rinse each part briefly in a separate interim rinse tank containing potable water to remove bulk detergent residues.
4. Rinsing Sequence
   1. Perform final rinsing of all product contact parts with purified water meeting Pharmacopeial standards.
   2. Rinse volume per batch of parts: minimum [rinse_volume_L], optimized to ensure removal of detergent and residues.
   3. Use fresh water for each rinse cycle; if recirculating rinse water is used, ensure water quality monitoring.
   4. Inspect rinse water visually and for conductivity/TOC to ensure cleanliness.
5. Drying
   1. Dry parts using filtered, compressed air or air dryers in a clean environment.
   2. Ensure complete drying with no residual moisture to reduce microbial risk and prevent cross-contamination.
   3. Use lint-free towels or clean air knives only where applicable for delicate components.
6. Reassembly of Machine Parts
   1. Reassemble all cleaned parts back onto the capsule polishing machine according to manufacturer’s guidelines.
   2. Verify correct and secure placement of all components to maintain machine functionality.
   3. Document completion of reassembly in cleaning validation logbook.
7. Visual Inspection
   1. Conduct a thorough visual inspection of all product contact parts post-cleaning and reassembly.
   2. Look for any residual product, stains, discoloration, or moisture.
   3. Document inspection outcomes and address abnormalities immediately.
   4. Only approve the machine for production when the visual inspection meets acceptance criteria for cleanliness.

Cleaning Procedure Critical Parameters and Limits

Sampling Plan for Cleaning Validation of Capsule Polishing Machine

Sampling Methodology

1. Use pre-moistened sterile swabs with sampling solvent recommended by analytical laboratory (e.g., water or buffer with surfactant) to maximize residue extraction.
2. Swab defined areas by wiping in a systematic S-pattern horizontally and vertically to cover the entire swab area.
3. Swabs collected immediately post-cleaning and prior to processing next batch.
4. Label swabs clearly with location, date/time, lot batch, and cleaner identity.
5. Store and transport samples to testing laboratory under controlled conditions to prevent contamination or degradation.

Sample Handling and Documentation

1. Complete chain-of-custody forms including signature of sample collector, transport personnel, and laboratory receiver.
2. Maintain sample integrity by appropriate storage (e.g., refrigeration at 2-8°C if delay before analysis is expected).
3. Record any deviations in the sample collection process and communicate to QA for assessment.

Site-specific inputs required

• Cleaning detergent name and concentration ([detergent_name], [detergent_concentration_% w/v])
• Soak time in detergent solution ([soak_time_minutes])
• Rinse water volume per batch of parts ([rinse_volume_L])
• Swab surface area per sample point ([swab_area_brush_cm2], [swab_area_chute_cm2], [swab_area_hopper_cm2], [swab_area_sieve_cm2], [swab_area_cover_cm2])

Swabbing and Sampling Plan

To demonstrate cleaning efficacy and validate the cleaning procedure, a robust sampling plan must be developed based on risk assessment, product characteristics, and equipment design.

Sampling Locations

Sampling Methodology

1. Use validated swabbing materials (e.g., pre-wetted swabs with specified solvent).
2. Swab the defined area in a consistent pattern (e.g., S-shaped overlapping strokes).
3. Collect rinse samples from final rinse water of parts where applicable to confirm absence of residues.
4. Label and transport samples under chain-of-custody conditions to the analytical laboratory.
5. Ensure sampling frequency is sufficient to represent routine cleaning (e.g., after initial validation, periodically for routine maintenance).

Analytical Testing and Residue Limits

Active Pharmaceutical Ingredient (API) Residue Analysis

API residues shall be quantified utilizing a validated analytical method specific to the product, such as HPLC or UV spectroscopy, depending on molecular properties.

Acceptance Criteria and Calculation:

The maximum allowable carryover (MACO) shall be calculated using the PDE/ADE approach as follows:

Site-Specific Inputs Required:

• Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) value of API (mg/day)
• Batch size of current product (capsules)
• Batch size of next product processed on equipment (capsules)

The residue limit per swab shall be normalized to sample area and recovery efficiency:

Swab limit (μg/cm²) = (MACO × Safety Factor × 1000) / Total swabbed surface area adjusted for recovery

Where Safety Factor is typically 2 for added conservatism.

Detergent Residue Limits

Detergent residues shall be evaluated by either Total Organic Carbon (TOC) or conductivity assays according to validated cleaning verification methods.

Criteria:

• TOC level must be below the established limit of [site-specific_command] ppm or equivalent as per method validation.
• Conductivity levels below [site-specific_conductivity_limit] µS/cm indicate negligible detergent residue.

Detergent limits are justified by method sensitivity, blank matrix data, and toxicological assessments.

Microbial Limits (If Applicable)

Microbiological testing should be considered based on risk assessment, particularly if capsule polishing machine contact parts are moist or prone to microbial harborage.

Acceptance criteria shall comply with internal specifications or compendial guidance.
Sampling should be performed post-cleaning and drying.

Cleaning Validation Protocol Outline

1. Pre-validation cleaning procedure documented and approved (refer to Part A).
2. Perform initial cleaning runs as per procedure with sampling at identified critical locations.
3. Analyze samples for API, detergent residues, and microbial counts if required.
4. Evaluate against acceptance criteria based on PDE/ADE MACO for API and validated detergent residue limits.
5. Perform at least three consecutive successful cleaning validation runs to demonstrate reproducibility.
6. Record all cleaning activities, sampling, and analysis data for traceability and audit readiness.
7. Implement routine periodic cleaning verification as per site quality strategy.
8. Investigate and re-validate if cleaning procedure or product batch size changes significantly.

Recovery, LOD, and LOQ Expectations

To ensure the reliability and sensitivity of analytical methods employed during the capsule polishing machine cleaning validation, recovery, Limit of Detection (LOD), and Limit of Quantification (LOQ) parameters must be rigorously qualified and monitored. These parameters safeguard the accuracy and precision of residue measurements on product contact parts.

Recovery: The expected recovery rate for swab/rinse sampling matrices should typically be between 80% and 120%. This range confirms that the analytical method efficiently extracts and detects residues without significant loss. Recovery studies should be performed using representative test articles spiked with known quantities of residues (API and detergent) on materials mimicking product contact parts.

LOD and LOQ: The LOD should be sufficiently sensitive to detect residue levels well below the safety threshold derived from Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) calculations, generally aiming for detection at or below 10% of the PDE-based Maximum Allowable Carry Over (MACO). The LOQ must enable precise quantification of residues at levels down to at least 30% of the PDE-based MACO, with acceptable relative standard deviations (typically ≤ 20%).

Site-specific inputs required:

• Analytical method validation data supporting recovery percentages on critical surfaces in the capsule polishing machine
• Identified LOD and LOQ values for both API and detergent residue assays (e.g., HPLC, TOC, conductivity)
• Sample matrix (swab/rinse) specifications and recovery study protocols

Acceptance Criteria Methodology: PDE/ADE-Based MACO Approach

The acceptance criteria for cleaning validation of the capsule polishing machine product contact parts employ a science- and risk-based approach centered on the PDE/ADE-based Maximum Allowable Carry Over (MACO) methodology. This methodology ensures patient safety by limiting cross-contamination to toxicologically acceptable levels while avoiding unnecessarily stringent criteria that do not contribute meaningfully to risk mitigation.

Overview of the PDE/ADE-Based MACO Calculation

MACO (mg) is calculated using the following formula:

Where:

• PDE (mg/day) is derived from toxicological data for the API of the previous product run on the machine.
• Batch Size (kg) and Daily Dose (kg) are expressed in consistent units, typically kilograms or grams, corresponding to manufacturing batch and patient dosing information respectively.

The MACO value represents the maximum quantity of residual active pharmaceutical ingredient (API) permitted to remain on equipment surfaces after cleaning without posing patient risk.

Example Calculation Structure (Placeholders for Site-Specific Input)

Translation to Swab/Rinse Acceptance Limits

The MACO value must be translated into analytical acceptance limits for swab and rinse samples taking into account the sampling surface area and recovery efficiency.

Fallback to Legacy Acceptance Criteria (If Required)

Where PDE or ADE data are unavailable or where regulatory guidelines specifically mandate, legacy acceptance criteria can be applied as a conservative fallback. Typically these utilize:

• Not more than 10 ppm (10 µg/g of residue) on sampled surfaces, or
• Carryover amount ≤ 1/1000th of the minimum therapeutic dose of the prior product.

These legacy values are less scientifically justified than PDE/ADE MACO but remain acceptable for legacy products and legacy regulatory expectations.

Detergent Residue Rationale and Acceptance

The cleaning process for the capsule polishing machine includes detergent usage to remove organic and inorganic contamination. Monitoring detergent residues is critical to avoid product contamination and potential patient safety risks.

Analytical Method Selection: Detergent residues will be assessed using validated Total Organic Carbon (TOC) or conductivity measurement methods, or a specific detergent assay (e.g., colorimetric assay, HPLC) depending on the detergent’s chemical nature.

Justification of TOC/Conductivity Methods: TOC is a robust universal indicator of residual organic material including detergents and is widely accepted for semi-quantitative monitoring. Conductivity is useful for ionic detergents with high charge density. Where specific detergent compounds dominate, targeted assay methods offer superior selectivity and specificity.

Acceptance Criteria: The acceptance criterion for detergent residues will be tied to the sensitivity and specificity of the chosen analytical method. Generally, detergent residue limits should be set at ≤ [detergent_LOQ] or < 1 mg per swabbed area, whichever is more conservative.

Site-specific inputs required:

• Name and chemistry of detergent ([detergent_name])
• Analytical method used for detergent residue detection and its LOD/LOQ values ([detergent_method])
• Specified maximum allowed detergent residue limits ([detergent_limit_mg/cm2])

Handling Deviations and CAPA

Any deviations observed during cleaning validation study execution, sampling, or analytical testing, including exceedance of acceptance criteria, must be documented and investigated following site Standard Operating Procedures.

1. Deviations Identification: Identification of deviation type (e.g., procedural non-compliance, analytical failure, out-of-specification (OOS) results) and immediate containment.
2. Root Cause Analysis: Comprehensive evaluation of possible causes such as incomplete cleaning procedure adherence, inadequate rinse volumes, or analytical variability.
3. Corrective and Preventive Actions (CAPA): Implementation of targeted corrective actions (e.g., retraining operators, equipment maintenance, optimizing detergent/rinse volumes) and preventive measures to prevent recurrence.
4. Revalidation Decision: Determine if partial or full revalidation of cleaning process or analytical methods is warranted based on root cause and risk assessment.

Deviation documentation and CAPA effectiveness reviews should be integrated into quality management system records.

Continued Verification Plan

Post-validation, continued verification ensures the sustained effectiveness of the cleaning process on the capsule polishing machine throughout routine production.

1. Frequency: Periodic sampling and testing should be performed at defined intervals, e.g., quarterly or batch-based after routine cleaning cycles.
2. Sampling: Follow the Sampling Plan defined in Part B, ensuring consistency with validated sampling locations and methods.
3. Analytical Testing: Analytical methods qualified during validation must be used unchanged but continuously verified for suitability (e.g., system suitability tests).
4. Data Trending and Review: Results must be trended with defined alert and action limits. Any positive trends towards acceptance limits require investigation and possible cleaning process adjustment.
5. Documentation: Continued verification results must be recorded, reviewed by Quality Assurance, and incorporated into annual Product Quality Reviews (PQRs).

Revalidation Triggers

Revalidation of the cleaning procedure and validation protocol shall be undertaken when any of the following events occur:

• Changes in equipment design or product contact parts impacting cleanability
• Switching to a different detergent or cleaning agent ([detergent_name])
• Introduction of a new product with significantly different PDE/ADE values or physical/chemical properties
• Significant process parameter changes such as cleaning time, temperature, or rinse volumes ([rinse_volume_L])
• Non-conformance in cleaning validation or continued verification sampling indicating process failure
• Implementation of changes based on CAPA investigations that impact cleaning effectiveness
• Periodic scheduled revalidation as required by site Quality Management System (e.g., every 3 years)

Annexures and Templates

The following annexures and templates support the capsule polishing machine cleaning validation and ongoing governance:

All annexures and templates should be permanently controlled documents under the site document management system.

Conclusion

The cleaning validation acceptance criteria and governance for the capsule polishing machine product contact parts have been established to prioritize patient safety while maintaining operational efficiency. Utilizing a PDE/ADE-based MACO methodology provides a risk-based, science-driven foundation for setting residue limits that reflect toxicological relevance. Rigorous qualification of recovery, LOD, and LOQ ensures method robustness, while detergent residue limits are supported by fit-for-purpose analytical techniques. Documented deviation management and CAPA maintain process reliability over time, complemented by a structured continued verification plan and defined revalidation triggers that uphold ongoing compliance. The comprehensive annexures and templates facilitate consistent execution and record-keeping, supporting audit readiness and regulatory expectations. This protocol aligns with current pharmaceutical industry best practices for oral solid dosage manufacturing and cleaning validation rigor.