Cleaning Validation Protocol for Coating Machine Product-Contact Surfaces in Transdermal Patch Manufacturing

Purpose and Scope

This Cleaning Validation Protocol outlines the structured approach for cleaning and validating the coating machine utilized in the manufacturing of transdermal patch dosage forms. Specifically, it addresses cleaning of all product-contact surfaces within the coating machine to ensure removal of active pharmaceutical ingredients (APIs), excipients, cleaning agents, and microbial contaminants to acceptable levels. This protocol establishes the foundation for demonstrating reproducible cleaning performance compliant with regulatory expectations and internal quality standards.

The scope includes all operations related to cleaning, sampling, analytical testing, and acceptance criteria of the coating machine used for transdermal patches at the facility. This encompasses equipment surfaces in direct contact with the product such as coating drums, applicators, feed system, and any internal surfaces potentially exposed to drug substances or formulation components.

This document is intended for use by quality assurance (QA), quality control (QC), validation engineering, production, and cleaning personnel involved in the cleaning validation lifecycle. Peripheral equipment or non-product-contact areas are excluded and managed under separate preventive maintenance or sanitation protocols.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

Given the chemicals involved in cleaning and the physical operations during cleaning of the coating machine, appropriate safety measures must be strictly observed. All personnel must wear appropriate PPE, including but not limited to:

1. Chemical-resistant gloves compatible with the cleaning agents used.
2. Protective goggles or face shield to prevent chemical splashes to eyes.
3. Lab coat or disposable coveralls to protect skin and clothing.
4. Respiratory protection where aerosolization or fumes from detergents are possible.
5. Non-slip safety shoes.

All cleaning agents’ Safety Data Sheets (SDS) must be reviewed before handling. Any incidents, spills, or exposures must be reported immediately to the Safety Officer and managed per site safety procedures.

Equipment Overview and Product-Contact Surfaces

The coating machine is designed for application of adhesive and active layers on transdermal patches and consists of multiple components where product-contact surfaces are critical for cleaning validation:

All above parts require validated cleaning to prevent cross-contamination or residual carryover of adhesive, APIs, or cleaning agents.

Cleaning Strategy Overview

The cleaning approach is designed to ensure reproducible removal of residual active and inactive materials to predetermined acceptance criteria focusing on safety and product quality. Key elements of the cleaning strategy include:

• Pre-Rinse: Removal of gross product residues using warm water or appropriate solvent per product formulation.
• Detergent Wash: Use of an approved cleaning agent [detergent_name], optimized for removal of adhesive polymers and hydrophobic APIs.
• Post-Rinse: Multiple rinses with purified water (PW) or water for injection (WFI) until residual detergent is below target limits.
• Use of CIP wherever feasible: For hard-to-reach internal surfaces to reduce manual intervention and variability.
• Manual Cleaning Steps: Accessible areas cleaned using specified swabs/sponges per procedure.
• Sampling Plan: Swab and rinse samples obtained from defined locations post-cleaning for analytical verification.
• Hold Times: Limits on duration between cleaning and subsequent use to avoid microbial growth or residue hardening.

Cleaning Agents and Tools List

Definition of Hold Times

Records and Forms List

Site-specific Inputs Required

• [detergent_name] – Name and specifications of cleaning detergent used in site cleaning procedure.
• [rinse_volume_L] – Total volume of rinse water(s) used per cleaning cycle.
• [swab_area_cm2] – Standardized swab sampling area for residue assessments.
• [rinse_fluid_type] – Specification of rinse fluid type (e.g., PW or WFI).
• [swab_type] – Approved swab/material type for residue and microbial sampling.
• [cleaning_tools_spec] – Specifications or brand names of brushes, sponges used during manual cleaning.
• [cip_parameters] – CIP temperature, duration, flow rates, and chemical concentrations unique to site.
• [dirty_hold_time_hours] – Maximum dirty hold time acceptable at site conditions.
• [clean_hold_time_hours] – Maximum clean hold time allowable before use.
• [sample_hold_time_hours] – Time limit ensuring sample integrity prior to analysis.

Cleaning Procedure for Coating Machine (Patches Product Contact Surfaces)

1. Pre-Clean Preparation
   1. Ensure that the coating machine is turned off and properly isolated from power sources per site safety protocols.
   2. Wear appropriate personal protective equipment (PPE) including gloves, safety goggles, and gown.
   3. Remove all loose product residues from the product contact surfaces using clean, disposable wipes or brushes.
   4. Document the cleaning batch and record pre-clean visual condition.
2. Disassembly of Product Contact Parts
   1. Carefully disassemble all removable product contact parts such as coating pans, spray nozzles, rollers, shields, and trays, following the manufacturer’s mechanical maintenance instructions.
   2. Place disassembled parts on a clean, designated stainless steel surface reserved for cleaned equipment parts.
   3. Ensure that sensitive components like sensors and electronics are protected from water or cleaning agents.
3. Washing Sequence
   1. Prepare the cleaning solution using [detergent_name] as per manufacturer’s recommended concentration and temperature.
   2. Immerse disassembled parts in the cleaning solution for a defined time period (e.g., 15 minutes) or manually scrub surfaces with brushes where immersion is not feasible.
   3. For fixed product contact surfaces that cannot be disassembled, apply detergent solution using automated spray or manual wiping ensuring coverage of all coating areas.
   4. Use mechanical scrubbers or brushes in a controlled, uniform manner to remove coating residues from all accessible surfaces.
4. Rinse Sequence
   1. Rinse all cleaned parts and fixed surfaces thoroughly using potable water or purified water (PW) system to remove residual detergent and product residues.
   2. Use [rinse_volume_L] liters per rinse cycle or until TOC/conductivity measurements indicate acceptable levels of residual cleaning agent.
   3. Repeat rinse cycles as necessary (typically two rinses are recommended) to meet acceptance limits.
5. Drying
   1. Air dry disassembled parts in a clean environment or use lint-free towels for drying if immediate reassembly is required.
   2. Use compressed air (filtered and oil-free) to facilitate drying of crevices and internal surfaces.
   3. Ensure no residual moisture remains as it may support microbial growth or interfere with coating application.
6. Reassembly
   1. Reassemble all components of the coating machine following the standard mechanical assembly procedure and torque specifications.
   2. Check all seals, gaskets, and fittings for integrity and cleanliness before final assembly.
7. Visual Inspection of Cleanliness
   1. Perform a detailed visual inspection of all product contact surfaces under adequate lighting conditions.
   2. Look for residues, streaks, stains, or any particulate contamination.
   3. Document the results with photographs where possible.
   4. If any evidence of contamination is observed, repeat cleaning procedures before proceeding with sampling for validation.

Cleaning Process Parameters and Limits

Sampling Plan for Cleaning Validation of Coating Machine

Sampling Locations and Rationale

Sample Collection Procedure

1. Wear powder-free gloves and change gloves between sample collections to prevent cross-contamination.
2. Use pre-moistened swabs with validated neutralizing agent or sterile water as per cleaning validation plan.
3. Swab the specified area using a defined pattern: horizontal strokes followed by vertical strokes, applying consistent pressure throughout.
4. Place swabs in sterile, labeled sample containers immediately after collection.
5. Label samples with unique identifiers using the format specified in the table, including machine ID, location, date, batch number, and sample number.

Chain-of-Custody and Sample Handling

1. Samples must be handed to trained QA personnel immediately following collection.
2. QA personnel shall log samples into the cleaning validation sample tracking system including date/time of receipt and condition of samples.
3. Samples must be stored at controlled temperature defined by analytical method requirements (typically 2–8 °C) until analysis.
4. Samples must be transported securely to the analytical laboratory, maintaining temperature controls during transit.
5. Any deviation or sample integrity issues must be documented and investigated per QA procedures.

Site-specific Inputs Required

• [detergent_name]
• [detergent_concentration]
• [cleaning_temperature]
• [rinse_volume_L]
• [swab_area_cm2]
• Machine ID
• Batch ID format

Cleaning Verification and Sampling

Visual Inspection

1. Inspect product contact surfaces for visible residues or soil after cleaning completion using appropriate lighting and magnification if needed.
2. Document visual inspection results on the Batch Cleaning Record.
3. If visible residues remain, repeat cleaning procedure before proceeding to analytical sampling.

Sampling Plan

1. Identify critical product contact surfaces of the coating machine for sampling including:
• Coating pans
• Spray nozzles
• Rollers and brushes
• Interior surfaces of chambers in contact with the transdermal patches
2. Define sampling locations based on worst-case product contact areas and residue retention potential.
3. Utilize surface swab sampling and/or rinse sampling techniques:
• Swab samples collected from defined surface area of [swab_area_cm2].
• Rinse samples collected from final rinse solution volume following [rinse_volume_L] standard rinse.
4. Use validated sampling materials and pre-cleaned containers to avoid cross-contamination or interference with analytical methods.

Sample Handling and Transportation

1. Label samples clearly with cleaning lot number, sampling site, date, and time.
2. Transport samples to the Quality Control laboratory promptly under controlled conditions to prevent contamination or degradation.
3. Maintain chain-of-custody documentation for sample traceability.

Analytical Testing Methods

Residue Analysis Methodology

1. Determine residual active pharmaceutical ingredient (API) and excipient levels using validated chromatography (e.g., HPLC) or spectroscopy methods specific to the patch formulation.
2. Measure detergent residues with appropriate total organic carbon (TOC) analysis, conductivity or detergent-specific assays as validated.
3. Confirm specificity, sensitivity, accuracy, and precision of all analytical methods within defined limits.

Acceptance Criteria

The following acceptance criteria based on PDE/ADE-based MACO approach are applied:

Legacy Acceptance Criteria (If PDE/ADE approach not applicable)

1. API Residue < 10 ppm per surface area unit or less than 1/1000 of the minimum therapeutic dose per cleaning event.
2. Detergent residues to meet site-established thresholds verified by TOC or specific detergent assay.

Documentation and Record-Keeping

1. Complete Cleaning Batch Records capturing cleaning dates, personnel, detergent batch numbers, cleaning parameters, and visual inspection outcomes.
2. Attach sampling logs with detailed sampling site descriptions, sample IDs, and times.
3. Include analytical testing reports with raw data, calculations, and acceptance evaluations.
4. Maintain the protocol deviation reports for any non-conformances during cleaning or sampling.
5. Retain all cleaning validation documentation per site archival requirements for regulatory inspections.

Site-Specific Inputs Required

• Name and formulation details of [detergent_name]
• Recommended cleaning solution concentration and temperature
• [rinse_volume_L] value per rinse cycle
• [swab_area_cm2] surface area for sampling
• Validated analytical method details and limits for API and detergent residues
• PDE/ADE values and batch size information for MACO calculations
• Microbial limit specifications if applicable

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

Analytical method validation is critical for establishing confidence in cleaning verification for the coating machine used in transdermal patch manufacturing. Recovery studies must demonstrate that the sampling and analytical methods can retrieve and quantify residues from all product contact surfaces with adequate precision and accuracy.

• Recovery: Recovery experiments shall be conducted by spiking defined levels of active pharmaceutical ingredient (API) and detergent residues on representative surfaces. Acceptance criterion for recovery is typically ≥ 70%, with an ideal target of ≥ 80%, to ensure accurate residue measurement.
• Limit of Detection (LOD): LOD shall be determined based on signal-to-noise ratio (typically 3:1) and defined in mass or concentration units. The LOD should be sufficiently low to detect residues below the calculated maximum allowable carryover (MACO).
• Limit of Quantitation (LOQ): LOQ will be established based on a higher signal-to-noise ratio (usually 10:1) and is the minimum quantifiable residue that provides acceptable accuracy and precision. LOQ must be below the MACO and cleaning acceptance criteria.

All analytical methods used for residue determination (e.g., HPLC, TOC, conductivity) must have documented LOD, LOQ, and recovery data incorporated into validation reports to assure compliance with acceptance criteria.

Acceptance Criteria Methodology (PDE/ADE MACO Approach)

The acceptance criteria for cleaning validation of the coating machine product contact surfaces for transdermal patches will utilize the PDE/ADE-based Maximum Allowable Carryover (MACO) method. This method is scientifically justified and aligns with ICH Q3A/Q3B and FDA guidance documents. The PDE/ADE MACO approach helps ensure that any residual cross-contamination poses no safety risk to subsequent batches.

Maximum Allowable Carryover (MACO) Calculation Structure

The MACO is calculated using the formula below:

MACO (mg) = (PDE or ADE) × (Minimum Batch Size of Next Product)

where:

• PDE (Permissible Daily Exposure): Maximum acceptable exposure per day for the API from an impurity/toxicology standpoint (e.g., mg/day).
• ADE (Acceptable Daily Exposure): Used if PDE data is unavailable or for non-toxic impurities.
• Minimum Batch Size: The lowest expected batch size (in kg or units) of the next product manufactured on the same equipment.

The acceptance criterion for residue per surface area (mg/cm²) is then determined by normalizing MACO to the sampling area:

Acceptance Criterion = MACO / (Sampling Area × Safety Factor)

• Safety Factor: Typically 10, to ensure an additional margin of safety.

Example Placeholder Calculation:

Legacy Acceptance Criteria (Fallback)

When toxicology or PDE/ADE data are not available, legacy acceptance criteria may be applied as a fallback method. The commonly used legacy criteria are:

• 10 ppm (parts per million) of the next product’s dose per surface area swabbed.
• 1/1000th of the lower therapeutic dose of the next product.

These legacy criteria should be clearly labeled as fallback and only applied after justified risk assessment and documentation stating why PDE/ADE data could not be used.

Detergent Residue Rationale and Acceptance

Detergent residues on the coating machine product contact surfaces can interfere with product quality and patient safety. Acceptance criteria for detergent residues must be scientifically justified based on the detergent chemistry and analytical method employed.

• Analytical Method Selection: Total Organic Carbon (TOC) or specific surfactant assays (e.g., HPLC for non-ionic detergents) are preferred for detergent residue quantification. Conductivity may be used for ionic detergents but requires well-defined correlation data between conductivity and detergent concentration.
• Acceptance Limits: Detergent residue limits are established by evaluating potential toxicological risk, irritation potential, and maximum allowable daily exposure. Limits must be consistent with residual detergent levels unlikely to affect product quality or patient safety.
• Rationale: The selected analytical method and acceptance criteria should be supported by scientific literature, vendor material safety data sheets (MSDS), and toxicological evaluations if available. The limits must also consider ingredient solubility, rinse efficiency, and analytical sensitivity.

Example detergent acceptance criteria placeholder:

Deviations and Corrective & Preventive Actions (CAPA)

Any deviations observed during cleaning validation execution or routine cleaning verification must be thoroughly documented and investigated. The deviation management process should ensure that root causes are identified and appropriate corrective and preventive actions are implemented.

• Common Deviations: Incomplete residue removal, sampling method failures, out-of-specification (OOS) analytical results, atypical equipment conditions.
• Investigation: Root cause analysis (RCA) using tools such as Fishbone diagrams or 5 Whys to identify systemic or human errors.
• CAPA Implementation: May include retraining personnel, modification of cleaning procedure or cleaning agents, equipment maintenance or redesign, enhanced sampling approaches.
• Verification: Post-CAPA cleaning validation runs or cleaning verification tests must confirm that corrective actions have resolved the issue.
• Documentation: All deviations and CAPA outcomes shall be documented in deviation reports and added to the cleaning validation lifecycle documentation for review.

Continued Verification Plan

To ensure ongoing control of equipment cleanliness and prevent cross-contamination, a continued verification program will be established as part of lifecycle management.

• Frequency: Periodic cleaning verification sampling and testing based on risk assessment (e.g., quarterly, biannually, or after maintenance/major cleaning changes).
• Sampling: Similar locations and sampling methods as defined in the validated Sampling Plan (Part B) to maintain consistency.
• Acceptance: Results must continually meet the validated acceptance criteria; any excursions trigger investigation and possibly revalidation.
• Trend Analysis: Data over multiple verification events should be trended to detect gradual deterioration or process drift.
• Reassessment: Continued verification programs must be reviewed regularly by Quality Assurance to ensure alignment with current manufacturing practices and regulatory expectations.

Revalidation Triggers

Revalidation of the cleaning procedure for the coating machine is mandated under the following circumstances to maintain control and regulatory compliance:

• Product Change: Introduction of new products with different APIs or change in formulation/strength.
• Cleaning Process Change: Modifications to detergents, cleaning steps, contact times, or equipment design.
• Equipment Repair or Replacement: Major repairs or substitution of critical components in the coating machine.
• Analytical Method Change: Significant changes in residue detection methods or acceptance criteria.
• Failed Verification: Repeat failures or OOS results during continued verification requiring root cause assessment.
• Regulatory or Internal Audit Findings: Recommendations or observations demanding reassessment of cleaning validation status.

Revalidation scope should be commensurate with the nature and extent of the change and must follow documented validation protocols per site SOPs.

Annexures and Templates List

For completeness and streamlined execution of cleaning validation and cleaning operation documentation, the following annexures and templates will be appended or referenced within the master validation folder:

• Additional documents such as Safety Data Sheets (SDS) for detergents and raw materials used in residues analysis should also be maintained.

Conclusion

The cleaning validation acceptance criteria for the transdermal patch coating machine shall primarily rely on the PDE/ADE-based MACO methodology. This approach offers a scientifically grounded, risk-based framework ensuring any residue left post-cleaning will not compromise patient safety or product quality. Analytical methods must be rigorously validated with demonstrable recovery, LOD, and LOQ suited to meet or surpass MACO limits. Detergent residues require separate, justified acceptance limits based on toxicological and analytical considerations. A robust deviation and CAPA management system ensures issues encountered during validation or production are promptly addressed. Continued verification of cleaning efficacy is essential for lifecycle control, and explicit revalidation triggers guarantee requalification upon significant changes or failures. The inclusion of annexures and templates supports thorough documentation and reproducibility of results. By adhering to these justifications and governance mechanisms, the cleaning validation program for the coating machine will sustain compliance with regulatory expectations and uphold pharmaceutical quality standards.