Tray Dryer Product Contact Trays: Cleaning Validation Protocol and Procedure Framework

Purpose and Scope

This document establishes the foundational elements of a cleaning validation protocol specifically tailored for the product contact trays of tray dryers utilized in the manufacture of oral solid dosage forms. Its objective is to define the necessary procedures, responsibilities, and materials required to ensure effective cleaning, thereby preventing cross-contamination and ensuring patient safety. This protocol supports validation activities aiming to demonstrate that cleaning processes consistently reduce residues—including active pharmaceutical ingredients (APIs), cleaning agents, and extraneous materials—to acceptable levels as per regulatory and quality standards.

The scope encompasses cleaning validation considerations for all tray dryer product contact trays within the manufacturing facility’s oral solid dosage production lines. It applies to all product variants processed using these trays and sets the groundwork for subsequent parts which detail acceptance criteria and sampling strategies.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

Personnel involved in cleaning activities must adhere to the following safety practices to mitigate exposure risks and ensure safe handling of cleaning agents and residues:

• Gloves: Chemical-resistant gloves compatible with the cleaning agents used.
• Safety goggles or face shield: To prevent splashes and aerosol exposure during cleaning.
• Protective clothing: Impermeable aprons or gowns to protect skin and prevent cross-contamination.
• Respiratory protection: If risk assessment identifies inhalation hazards, appropriate respirators must be worn.
• Footwear: Closed, non-slip, chemical-resistant shoes to maintain workplace safety.

All personnel must receive training on Material Safety Data Sheets (MSDS) of the detergents and chemical agents utilized in cleaning. Emergency protocols for spills or exposure must be clearly communicated.

Equipment Overview and Product Contact Parts

The tray dryer utilized in oral solid dosage manufacturing comprises multiple product contact trays where the product resides during drying cycles. These trays represent critical cleaning interfaces and must be validated thoroughly.

The cleaning focus is on the product contact trays themselves, notably surfaces exposed directly to API or excipient residues during drying.

High-Level Cleaning Strategy Overview

The cleaning approach incorporates a multi-stage process emphasizing removal of residual API, cleaning agents, and potential microbial contaminants through validated procedures. It aims to minimize cross-contamination risks and maintain product quality.

• Initial Dry Cleaning: Manual removal of gross residues from trays using brushes or squeegees.
• Detergent Cleaning: Application of validated detergent [detergent_name] to dissolve and remove chemical residues and product soil.
• Rinsing: Multiple rinses using purified water ([rinse_volume_L] per rinse) to ensure detergent and residue removal.
• Final Wiping/Drying: Use of lint-free wipes and air drying to prevent recontamination.

This approach may include ultrasonic or spray-based cleaning if available and justified in the final protocol.

Cleaning Agents and Tools List

Cleaning Tools:

• Soft-bristle brushes sized for tray crevices
• Squeegees for scraping residues
• Swabs for sampling validation
• Spray bottles or delivery system for detergent and rinse water

Hold Time Definitions

Site-specific environmental conditions, microbial risk assessment, and scheduling must inform these hold times.

Records and Forms

Documentation is critical for demonstrating compliance and ensuring traceability throughout the cleaning validation lifecycle. The following records and forms are recommended for incorporation into quality systems:

• Cleaning Validation Protocol Approval Form
• Cleaning Procedure (SOP) Documents
• Cleaning Batch Records including Detergent Lot and Usage
• Cleaning Swab/Rinse Sample Collection Records
• Analytical Test Reports (e.g., Residual API, Detergent by TOC or Conductivity, Microbial Test Reports)
• Cleaning Validation Summary Reports
• Deviation and CAPA Forms for Cleaning Process Failures
• Training Records for Personnel performing cleaning

Site-Specific Inputs Required

• Identification of [detergent_name] including concentration and supplier
• Defined [rinse_volume_L] per cleaning cycle
• Exact [swab_area_cm2] used for residue sampling
• Maximum allowable [dirty_hold_time_hours] and [clean_hold_time_hours]
• Equipment specific details such as tray dimensions and material confirmation
• Validated analytical methods for detergent residue and API detection
• Microbial cleaning risk assessment and thresholds, if applicable
• Personnel PPE availability and safety requirements per site hazard analysis

Tray Dryer (Product Contact Trays) Cleaning Procedure

1. Pre-Cleaning Preparation:
   • Ensure the tray dryer is fully stopped and disconnected from power sources to prevent accidental startup.
   • Wear appropriate personal protective equipment (PPE) including gloves, goggles, and cleanroom garments.
   • Remove all residual product manually from trays and product contact surfaces using lint-free cloths.
   • Prepare cleaning agents and rinse water at required concentrations and volumes as per site-specific procedure.
2. Disassembly of Product Contact Trays:
   • Carefully remove product contact trays from the tray dryer frame.
   • Place trays in a designated clean area for washing to prevent cross-contamination.
   • Document tray serial or batch number if applicable for traceability.
3. Washing Procedure:
   • Prepare a washing solution using [detergent_name] at the concentration of [detergent_concentration%] as specified by the detergent manufacturer.
   • Submerge trays in the detergent solution or apply detergent via automated spray equipment ensuring complete coverage of all product contact surfaces.
   • Maintain detergent contact for a minimum of [contact_time_minutes] minutes at a temperature of [wash_temperature_°C].
   • For manual cleaning, scrub trays thoroughly using approved brushes or non-abrasive scrubbers suitable for stainless steel surfaces.
4. Rinsing Sequence:
   

   Step	Description	Parameter	Site-Specific Input
   First Rinse	Rinse trays with potable water to remove gross detergent residues.	Rinse volume: [rinse_volume_L]; Temperature: [rinse_temperature_°C]	Rinse volume and temperature
   Second Rinse	Perform rinse with purified water to remove residual detergent and particulates.	Rinse volume: [rinse_volume_L]; Temperature: [rinse_temperature_°C]	Rinse volume and temperature
   Final Rinse	Conduct a final rinse with WFI (Water for Injection) or equivalent water to ensure removal of all residues.	Rinse volume: [rinse_volume_L]; Temperature: [rinse_temperature_°C]	Rinse volume and temperature

5. Drying Procedure:
   • Dry trays using validated hot air or clean compressed air drying systems.
   • Ensure drying temperature does not exceed [max_drying_temperature_°C] to avoid tray deformation.
   • Drying duration to be at least [drying_time_minutes] minutes or until there is no visible moisture.
6. Reassembly:
   • Once trays are dried, reassemble the trays into the tray dryer frame following manufacturer’s instructions and SOP.
   • Ensure all fastening points and seals are securely replaced and inspected.
   • Confirm tray dryer is restored to operational readiness status with no foreign material presence.
7. Visual Inspection:
   • Perform visual inspection of all product contact trays and associated surfaces under adequate lighting.
   • Look for stains, residues, discoloration, physical damage, or corrosion.
   • Record results in cleaning log, rejecting trays showing defects or residual contamination.

Sampling Plan for Cleaning Validation

Sampling Locations and Rationale

Number of Swabs and Sampling Frequency

1. A minimum of [minimum_swab_count] swabs per batch cleaning cycle shall be collected.
2. Swabs shall be taken from distinct locations outlined above to encompass maximum risk areas.
3. Sampling shall be performed immediately after the final rinse and drying step, prior to reassembly to ensure residues are detectable before reuse.
4. Swabbing will be duplicated on at least three consecutive cleaning cycles during validation to establish reproducibility.

Sample Labeling and Chain-of-Custody

All samples must be documented in a sample log sheet which maintains the chain-of-custody from collection through transportation and analysis compliant with site SOPs.

Sample Handling and Transport

1. Immediately place swab samples in sterile, sealed containers or bags labeled as above to prevent contamination or loss.
2. Store and transport samples to the analytical laboratory under controlled conditions (typically room temperature unless method-specific conditions apply).
3. Samples should be analyzed as soon as possible but no later than [maximum_hold_time_hours] hours after collection to ensure sample integrity.
4. Maintain documentation of sample receipt, storage, and disposal in accordance with GMP requirements.

Site-Specific Inputs Required

• [detergent_name] – name and specification of detergent used for washing
• [detergent_concentration%] – detergent concentration for wash solution
• [contact_time_minutes] – minimum detergent contact time during wash
• [wash_temperature_°C] – temperature maintained during washing
• [rinse_volume_L] – liters of water per rinse cycle
• [rinse_temperature_°C] – temperature of rinse water
• [max_drying_temperature_°C] – maximum drying temperature to prevent tray damage
• [drying_time_minutes] – duration of drying cycle
• [swab_area_cm2] – defined surface area swabbed per sample location
• [minimum_swab_count] – minimum number of swabs per cleaning validation cycle
• [maximum_hold_time_hours] – maximum allowable time from sampling to analysis

Cleaning Validation Acceptance Criteria

PDE/ADE-Based MACO Methodology for Residue Limits

The Maximum Allowable Carryover (MACO) limit for tray dryer product contact trays shall be calculated based on Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) values for the product. This scientifically justified approach ensures patient safety and regulatory compliance. The following formula defines the MACO:

The MACO will be converted to mg/cm² based on the total product contact surface area of the trays, which must be established during equipment qualification.

Analytical Acceptance Limits for Product Residues

Product residues on trays after cleaning shall not exceed the MACO limit calculated above, expressed on a surface area basis. Residue testing shall employ validated analytical methods with limits of quantitation lower than the MACO threshold.

• Sampling Method: Swab sampling or rinse sampling from product contact trays using validated techniques.
• Analytical Method: HPLC, UV, TOC or other product-specific validated test methods.
• Acceptance Criterion: Residue < MACO mg/cm²

Detergent Residue and Rinse Water Acceptance Criteria

Residues from cleaning agents must meet acceptance limits established by validated detection methods suitable for the detergent formulation used.

Site-specific input list:

• [Detergent_Acceptance_Criterion]
• [Conductivity_Max_μS/cm]

Microbial Limits (Risk-Based)

Microbial limits may be applied only if the cleaning process and equipment represent a risk of microbial contamination in downstream product stages. Limits shall align with pharmacopeial requirements or internal risk assessments. If applied:

• Sampling: Swab samples from product contact trays after cleaning and drying.
• Acceptance Criteria: Total aerobic microbial count (TAMC) ≤ [TAMC_limit] CFU/100cm², Total yeast and mold count (TYMC) ≤ [TYMC_limit] CFU/100cm².

Site-specific inputs required:

• [TAMC_limit]
• [TYMC_limit]

Sampling Plan

Sampling Locations

Sampling shall focus on the most difficult-to-clean and highest risk areas identified during risk and equipment assessment to ensure representative validation results.

Sampling Frequency and Number of Samples

1. At least three swab samples shall be collected per validation run, targeting diverse tray locations.
2. Sampling shall be performed after completion of cleaning and drying process before reassembly.
3. Repeated sampling may be required based on product change, detergent change, or process modifications.

Sample Handling

1. Swabs shall be immediately transferred to sterile containers with suitable solvent or diluent for extraction.
2. Samples must be labeled clearly with date, batch, equipment ID, sampling location, and operator identifiers.
3. Transport samples promptly to the QC laboratory under controlled conditions to avoid degradation or contamination.

Recovery, LOD, and LOQ Expectations

For an inspection-ready tray dryer cleaning validation protocol, it is critical to characterize sample recovery efficiencies, limits of detection (LOD), and limits of quantification (LOQ) for the analytical methods employed in residue determination. Recovery studies shall be performed using representative coupons or swabs covering the product contact trays’ surfaces outlined in the Sampling Plan defined in Part B.

• Recovery: Spike-and-recovery experiments should be conducted at multiple concentration levels representative of expected residue levels, typically including the acceptance criteria range. Recovery rates should ideally fall between 80% and 120%. Values outside this range require method optimization or justification for acceptance.
• LOD: The LOD must be sufficiently low to detect residues at levels below one-third of the maximum allowable carryover limit calculated via the PDE/ADE MACO approach, ensuring early detection of non-compliance.
• LOQ: The LOQ should be validated at no higher than the acceptance limit derived from the PDE/ADE MACO, guaranteeing precise quantification of residues at levels of regulatory concern.

Typical LOD and LOQ definitions are based on signal-to-noise criteria (LOD is commonly S/N ≥ 3; LOQ is S/N ≥ 10) or standard deviation of the response and slope of calibration curves, as per ICH Q2(R1) guidelines. All limits should be documented and traceable.

Acceptance Criteria Methodology Using PDE/ADE-Based MACO

The acceptance criteria for tray dryer cleaning validation are primarily established using Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) concepts coupled with the Maximum Allowable Carryover (MACO) calculation. This approach ensures patient safety by quantitatively limiting residue transfer based on toxicological thresholds rather than arbitrary numerical limits.

Conceptual Framework

MACO is derived to prevent cross-contamination of the next manufactured product by limiting the chemical carryover from the cleaning process. The general formula for MACO is:

Key parameters to define for MACO calculation include:

• PDE/ADE: Obtain from toxicological assessment or regulatory guidelines (e.g., ICH Q3A/B, CPMP, or published literature). Insert PDE placeholder as [PDE_mg_per_day].
• Batch size: Batch or lot size for the next scheduled product manufacturing campaign, expressed as [Next_Batch_Size_kg].
• Daily dose: Therapeutic dose of the prior product in mg/day, entered as [Prior_Daily_Dose_mg].

Example MACO Calculation

The resulting MACO value is then converted to an acceptance limit relating to the surface area or sample area analyzed during validation sampling, using the formula:

Note: For swab and rinse sampling, acceptance criteria must be adjusted for sampling recovery efficiencies and analytical sensitivity.

Legacy Acceptance Criteria (Fallback)

Where PDE/ADE data are unavailable, legacy acceptance criteria may be applied as a conservative fallback, including:

• A maximum of 10 ppm (mg/kg) of residue on equipment surfaces.
• Acceptance of residues not exceeding 1/1000th of the prior product dose, as per common industry practice.

These legacy criteria should only be utilized in the absence of toxicological data and must be clearly identified as such in the documentation.

Detergent Residue Rationale

Detergent residues must be monitored and limited to prevent patient exposure to cleaning agents and avoid interference with subsequent product manufacture. The rationale for detergent acceptance limits is based on the analytical method employed and its sensitivity.

• Analytical Method Linkage: Residual detergent acceptance criteria shall be defined relative to the validated method used: for example, Total Organic Carbon (TOC) testing, conductivity analysis, or specific detergent assay (e.g., HPLC, colorimetry).
• TOC-Based Limits: If TOC is used, detergent residues should be limited to a pre-established threshold (e.g., [TOC_limit_mg/cm2]) consistent with safe exposure and manufacturing requirements. The TOC threshold should be justified based on typical detergent composition and safety data.
• Specific Detergent Assays: Where a targeted detergent assay exists, limits should be based on toxicological acceptability related to the detergent components, employing either PDE/ADE or maximum residue limits as appropriate.
• Justification: The rationale for setting a detergent residue limit is derived from safety data such as Material Safety Data Sheets (MSDS), supplier toxicological profiles, and compatibility with the next product to be manufactured.

Deviations and Corrective and Preventive Actions (CAPA)

Any deviations from the validated cleaning procedure or limits established within this protocol must be documented, investigated, and addressed through appropriate CAPA initiatives.

• Types of Deviations: Deviations may include but are not limited to failure to meet acceptance criteria in residue analysis, incomplete cleaning steps, or equipment damage affecting cleaning efficacy.
• Investigation: Root cause analysis should be carried out to identify why the deviation occurred, whether due to procedural non-compliance, method failures, or equipment inadequacies.
• CAPA Actions: Actions may range from retraining personnel, revising cleaning processes, modifying equipment, or updating validation protocols.
• Documentation: All deviation investigations and CAPA implementation must be documented per GMP requirements, with clear linkage to batch records and cleaning logs.
• Revalidation Trigger: Significant changes to cleaning processes or corrective actions must trigger partial or full revalidation of the tray dryer cleaning method.

Continued Verification Plan

Ongoing verification of cleaning efficacy is essential to ensure the validated cleaning process remains effective throughout routine manufacturing operations. The continued verification plan should include:

• Periodic Sampling: Defined intervals, such as quarterly or semi-annually, to collect swab or rinse samples from high-risk product contact tray areas as identified in the Sampling Plan defined in Part B.
• Analytical Testing: Application of validated residue tests consistent with the original validation, ensuring detection of product, detergent, and microbial residues as applicable.
• Trend Analysis: Trending of cleaning residue data over time to identify potential process drifts or contamination trends.
• Documentation: Maintaining records aligned with change control and quality systems for traceability and audit readiness.
• Escalation Criteria: Criteria for investigation when residue levels approach or exceed acceptance limits, triggering CAPA or revalidation as necessary.

Revalidation Triggers

Revalidation of the tray dryer cleaning process is required under the following conditions:

• Changes in equipment design or materials of construction affecting cleaning accessibility or efficacy.
• Introduction of a new detergent or cleaning agent (change in composition or concentration).
• Change in the prior or subsequent product formulation, dose, or toxicological profile affecting PDE/ADE or MACO calculations.
• Modifications to the cleaning procedure steps (time, temperature, rinse volume, etc.).
• Failure to meet acceptance criteria in routine continued verification testing.
• Deviations or adverse events that impact the validated cleaning process.
• Regulatory agency request or changes in applicable guidelines and standards.

Annexures and Templates

The following annexures and templates shall accompany this protocol and serve as integral tools for execution and documentation:

• Annexure A: Sample Recovery Study Report Template
• Annexure B: Analytical Method Validation Summary (LOD, LOQ, Linearity, Precision)
• Annexure C: PDE/ADE Data Source and Toxicological Justification Documentation
• Annexure D: MACO Calculation Worksheet with Placeholders
• Annexure E: Cleaning Procedure Checklist and Compliance Log
• Annexure F: Cleaning Validation Sampling Log (linked to Sampling Plan in Part B)
• Annexure G: Deviation and CAPA Form Template
• Annexure H: Continued Verification Plan and Trending Report Template
• Annexure I: Change Control & Revalidation Checklist for Cleaning Process
• Annexure J: Analytical Data Review and Approval Form

These templates shall be customized with site-specific details prior to implementation and regularly reviewed as part of the quality management system.

Site-Specific Inputs Required

• [detergent_name]
• [rinse_volume_L]
• [swab_area_cm2]
• [PDE_mg_per_day]
• [Next_Batch_Size_kg]
• [Prior_Daily_Dose_mg]
• [TOC_limit_mg/cm2]

Conclusion

This section establishes a scientifically justified and regulatory-aligned framework for acceptance criteria and governance of the tray dryer (product contact trays) cleaning validation process. Implementing a PDE/ADE-based MACO methodology ensures robust patient safety by quantifying permissible residue carryover grounded in toxicological limits rather than arbitrary thresholds. Comprehensive characterization of recovery, LOD, and LOQ supports the reliability of residue detection methods. The rationale for detergent residue limits ensures consumer protection from cleaning agent residues with confirmed analytical traceability. Rigorous governance through deviation management, continued verification, and defined revalidation triggers safeguards ongoing cleaning efficacy and compliance. The included annexures and templates provide structured documentation tools to maintain an inspection-ready state and facilitate continuous improvement in cleaning validation practices. Adherence to these guidelines will assure that the tray dryer cleaning validation remains effective, reproducible, and fully aligned with GMP and regulatory expectations.