Dispensing Booth Cleaning Validation Protocol for Product Contact Surfaces in Oral Solid Dosage Manufacturing

Purpose and Scope

The purpose of this document is to establish a validated cleaning protocol and acceptance criteria specifically for the dispensing booth product-contact surfaces used in the manufacturing of oral solid dosage (OSD) forms. This protocol ensures that residues from previous batches, detergents, and microbial contaminants are effectively removed, thereby preventing cross-contamination and assuring product quality and patient safety.

This protocol applies to the cleaning validation activities related to dispensing booths in facilities manufacturing solid oral dosage forms, including tablets and capsules. It covers the cleaning procedure, cleaning agents, equipment used, validation sampling plans, and criteria for acceptance based on toxicological risk assessment and applicable regulatory guidance.

Use of this document is intended for Quality Assurance, Quality Control, Validation, Production, and Engineering personnel involved in cleaning validation and cleaning operations of dispensing booth surfaces.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

Personnel involved in cleaning and validation activities must adhere to site-specific safety protocols and wear necessary PPE to safeguard health and prevent contamination. Recommended PPE includes:

• Disposable gloves resistant to detergents and solvents
• Protective gowns or coveralls
• Face masks or respirators (as dictated by detergent chemical hazards or particulate concerns)
• Safety goggles or face shields
• Hairnets and shoe covers

Chemical Safety Data Sheets (SDS) for each detergent and cleaning agent must be reviewed and made available at the cleaning site. Procedures for spill management, ventilation, and first aid must be strictly followed.

Equipment Overview and Product Contact Parts

The dispensing booth is a critical component for material handling in manufacturing oral solid dosages. It consists of:

• Work Surface Panels: Stainless steel or GMP-grade polymer panels that come into direct contact with powders or intermediate products.
• Dispensing Funnels and Hoppers: Funnels guiding materials into packaging or processing containers; constructed from stainless steel or food-grade plastics.
• Glove Ports and Sleeves: Disposable or reusable gloves attached to the booth structure maintaining aseptic conditions but may have product contact.
• Windows and Viewing Panels: Typically glass or polycarbonate; may contact powder dust during dispensing.
• Airflow and Filtration Grills: Located inside the booth, contact minimal product; included in cleaning validation risk assessment.

Cleaning validation focuses primarily on surfaces with direct product contact including work surfaces, funnels, hoppers, and gloves in the dispensing area. Non-product contact parts such as outer surfaces or external control panels are excluded unless risk-assessed otherwise.

Cleaning Strategy Overview

The cleaning strategy aims to effectively remove residues of active pharmaceutical ingredients (APIs), excipients, allergens (if any), cleaning agents, and microbial contaminants from the booth surfaces. Key features include:

• Dry Removal: Manual removal of visible residues by brushing, wiping, or vacuuming prior to wet cleaning.
• Detergent Wash: Application of an approved pharmaceutical detergent ([detergent_name]) at a validated concentration and contact time to solubilize residues.
• Rinse Cycles: Multiple rinses with purified water ([rinse_volume_L] per rinse) to remove detergent and residues.
• Post-clean Inspection: Visual inspection and swab or rinse sampling for analytical confirmation.
• Sampling Plan: Targeted swabbing of high-risk surfaces ([swab_area_cm2]) based on worst-case residue locations identified during risk assessment.
• Hold Times: Dirty hold time limits the maximum interval between product completion and cleaning start; Clean hold time limits allowable delay between cleaning and next use or validation sampling.

The protocol utilizes a risk-based, science-driven approach such as PDE/ADE-based MACO calculations to establish acceptable residue limits to ensure product safety.

Cleaning Agents and Tools List

Hold Times Definitions

Records and Forms List

• Dispensing Booth Cleaning Procedure Log
• Cleaning Validation Sampling Log
• Analytical Test Result Reports (Swab and Rinse Testing)
• Cleaning Validation Protocol and Report
• Cleaning Agent Preparation Records
• Equipment Cleaning and Maintenance Logs
• Safety Data Sheet (SDS) File for Cleaning Chemicals
• Deviation and Change Control Documents related to cleaning procedures

Site-specific Inputs Required

• Approved detergent name and formulation: [detergent_name]
• Purified water rinse volume per rinse step: [rinse_volume_L]
• Swab sample size in cm²: [swab_area_cm2]
• Dirty hold time limit (hours): [max_dirty_hold_time_hours]
• Clean hold time limit (hours): [max_clean_hold_time_hours]
• Materials of construction of dispensing booth surfaces (e.g., stainless steel grade, polymer type)
• Operating parameters such as cleaning temperature and detergent concentration
• Analytical method(s) planned for detergent residue evaluation (e.g., TOC, conductivity, HPLC)
• Product-specific PDE/ADE values required for MACO calculations

Dispensing Booth (Product Contact Surfaces) Cleaning Procedure

1. Pre-cleaning Preparation
   1. Don appropriate personal protective equipment (PPE) including gloves, gown, mask, and hair cover.
   2. Ensure dispensing booth is powered off and all product materials removed from the booth and adjacent areas.
   3. Check availability and expiry dates of cleaning agents [detergent_name], rinse water quality, and sterile wipes/sampling materials.
   4. Verify documentation and cleaning log sheets are ready for recording cleaning parameters and observations.
2. Disassembly of Detachable Product Contact Components
   1. Carefully disassemble all detachable product contact parts such as bulk hoppers, feed chutes, trays, and inlet/outlet guards according to the manufacturer’s instructions or SOP.
   2. Place disassembled parts on sanitized racks or trays to avoid contamination.
   3. Document disassembly completion and visually inspect parts for residual product or debris.
3. Cleaning of Booth Product Contact Surfaces
   1. Apply pre-approved detergent solution [detergent_name] at manufacturer recommended concentration using spray or wipe method focusing on all product contact surfaces.
   2. Allow detergent contact time of [detergent_contact_time_minutes] minutes to ensure effective soil removal.
   3. Use manual scrubbing tools (non-abrasive brushes or wipes) to dislodge adhered residues on hard-to-clean surfaces and corners.
   4. Clean under and behind removable components and within crevices where product residues accumulate.
4. Rinse Sequence
   1. Rinse all cleaned surfaces with potable water filtered to pharmaceutical grade quality (e.g., purified water [rinse_volume_L]) to remove detergent residues.
   2. Repeat rinse if necessary to ensure no visible foam or residues remain.
   3. Remove and rinse detachable parts separately before drying.
   4. Confirm rinse water conductivity or TOC is within acceptable limits immediately after rinsing to justify cleaning completion.
5. Drying
   1. Dry all cleaned and rinsed surfaces using lint-free sterile wipes or filtered air dry to prevent microbial growth.
   2. Ensure no water droplets remain on surfaces or in crevices after drying step.
   3. Record drying time duration and method used.
6. Reassembly
   1. Reassemble the detached components carefully ensuring correct alignment and secure fitting as per equipment manual.
   2. Document completion of reassembly steps including any deviations or repairs.
7. Visual Inspection
   1. Perform a thorough visual examination of the entire dispensing booth product contact surfaces for cleanliness, damage, corrosion, or wear by trained personnel under adequate lighting.
   2. Use magnification tools if needed to confirm absence of residues or foreign materials.
   3. Document visual inspection results and obtain approval signatures.

Cleaning Parameters and Control Table

Sampling Plan for Dispensing Booth Cleaning Validation

Additional Sampling Considerations

1. Swab Methodology: Use validated swabbing materials and techniques to recover residues quantitatively from selected sites. Swabbing must be performed by trained personnel to ensure reproducibility.
2. Number of Samples: Minimum of two swabs per critical surface to ensure representative sampling unless otherwise justified by risk assessment.
3. Sample Transport: Samples must be routed to analytical laboratories within [max_transport_time] hours and stored at appropriate conditions (e.g., refrigerated if required) to prevent degradation or contamination.
4. Sample Documentation: Each sample container must include unique identification code linking it to sampling location, date, and operator in sampling log to maintain chain-of-custody integrity.
5. Sampling Timeframe: Sampling to be performed immediately after completion of cleaning, drying, and visual inspection to capture true residual levels.
6. Additional Rinse Water Sampling: Collect rinse water samples during final rinse from various booth outlets to verify detergent removal through TOC and conductivity analysis; labeled and handled as per solids surface swabs.

Site-Specific Inputs Required for Sampling Plan Implementation

• Detergent identifier and concentration ([detergent_name], [detergent_concentration])
• Detergent contact time parameters ([detergent_contact_time_minutes])
• Volume and quality limits for rinse water ([rinse_volume_L], [max_conductivity], [TOC_limit])
• Swab sampling surface area size per site ([swab_area_cm2])
• Maximum sample transportation time ([max_transport_time])
• Drying time minimums and methods ([dry_time_minutes])

Visual Inspection

1. Conduct a thorough visual examination of all cleaned and reassembled product contact surfaces under adequate lighting conditions.
2. Check for residual product, stains, discoloration, or moisture presence on all surfaces and components.
3. Inspect seals, joints, and hard-to-reach areas for cleanliness and integrity.
4. Document findings on the cleaning log sheet, noting any abnormalities or need for re-cleaning.

Sampling Plan for Cleaning Validation

Sampling Locations

Identify and document representative sampling locations on dispensing booth product contact surfaces based on:

• Areas with highest risk of product residue accumulation (e.g., feed chutes, contact trays, seals).
• Sites difficult to clean thoroughly, including crevices and joints.
• Detachable parts with direct product contact surfaces.

Sampling locations must cover both fixed and removable components as per the attached booth schematic and risk assessment.

Sampling Methods

1. Swab Sampling: Use validated sterile swabs wetted with extraction solvent or aqueous neutralizing agent to collect residues from predefined [swab_area_cm2] cm² areas.
2. Rinse Sampling (if applicable): Collect rinse water used during final rinse from targeted zones to detect residual detergent or product residues.
3. Surface Wipe Sampling: Use moistened sterile wipes for extended surface areas when swabbing is impractical.

Sampling Frequency

• Initial cleaning validation campaign: sample each identified critical site at least in triplicate per cleaning cycle demonstration.
• Routine monitoring: sample high-risk locations based on established risk assessment and historical data.

Analytical Methods and Acceptance Criteria

Residue Limits Using PDE/ADE-Based MACO Methodology

Define acceptance criteria for residual product on dispensing booth surfaces applying the Maximum Allowable Carry Over (MACO) based on the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) values:

Swab/Extraction recovery factors must be considered in final calculations.

Detergent Residue Limits

Detergent residues must be controlled by validated analytical methods such as Total Organic Carbon (TOC) or conductivity measurements:

1. Define detergent-specific TOC or conductivity limits based on cleaning agent properties and toxicological assessments.
2. Establish acceptance criteria, for example, TOC < [TOC_limit] ppm or conductivity < [conductivity_limit] µS/cm.
3. Confirm detergent residues are below limits prior to product contact.

Microbial Limits (Risk-Based)

If risk assessment identifies potential microbiological contamination, the following may be applied:

• Total Aerobic Microbial Count: Limit not to exceed [TAMC_limit] CFU/100 cm².
• Absence of specified pathogens as per company microbiological standards.

Microbial testing is optional, based on product risk and process requirements.

Documentation and Records

1. Complete cleaning log sheets capturing all cleaning parameters, personnel, start/end times, and deviations.
2. Record disassembly, reassembly, and visual inspection data.
3. Document sampling activities including location, method, date/time, and personnel.
4. Retain analytical test reports for residue and detergent determinations with batch numbers and equipment IDs.
5. Investigate and document corrective actions if acceptance criteria are not met.

Site-Specific Inputs Required

• [detergent_name]: Specify detergent product and concentration.
• [detergent_contact_time_minutes]: Contact time for detergent application.
• [rinse_volume_L]: Volume and quality of rinse water used.
• [swab_area_cm2]: Defined swabbed surface area for sampling.
• [PDE_value], [Batch_size], [Min_daily_dose]: API-specific toxicology and manufacturing parameters.
• [TOC_limit], [conductivity_limit]: Analytical acceptance levels for detergent residues.
• [TAMC_limit]: Microbial limit if applicable.

Analytical Method Performance and Validation

The analytical methods selected for residue detection from the dispensing booth product contact surfaces must undergo thorough validation to ensure reliability, sensitivity, and specificity in accordance with ICH Q2(R1) guidelines. Key method performance parameters include recovery, limit of detection (LOD), and limit of quantitation (LOQ), which directly impact the accuracy of the cleaning validation outcomes.

Recovery

Recovery studies shall be conducted to evaluate the efficiency of the analytical method in extracting the residual product or detergent from swab samples. A target recovery rate of ≥ 70% is recommended to ensure meaningful interpretation of residue results. Recovery experiments involve spiking known concentrations of the active pharmaceutical ingredient (API) or detergent onto representative product contact surfaces, followed by swabbing and analytical quantitation.

Limit of Detection (LOD) and Limit of Quantitation (LOQ)

The determined LOD and LOQ must be below the Maximum Allowable Carryover (MACO) limits, providing confidence that residue levels approaching or exceeding acceptance criteria will be detectable and quantifiable. The LOD is the lowest concentration at which the analyte can be reliably detected, while the LOQ is the lowest concentration at which the analyte can be quantified with acceptable accuracy and precision.

Acceptance Criteria Methodology

The acceptance criteria for product residues in dispensing booth cleaning validation shall primarily be based on the PDE/ADE-based Maximum Allowable Carryover (MACO) methodology, aligning with industry best practices and regulatory expectations. This scientifically justified approach incorporates toxicological thresholds, product potency, batch sizes, and safety margins to define residue limits that ensure patient safety and cross-contamination control.

MACO Calculation Structure

MACO = (PDE × Batch_Size × 1,000,000 μg/mg) / Surface_Area 

Where:

• PDE is derived from toxicological data, correlated to the maximum tolerated residue on the next product to be manufactured in the booth.
• Batch_Size is the minimum batch size of the subsequent product, ensuring conservative safety margins.
• Surface_Area corresponds to all accessible product contact surfaces inside the dispensing booth considered in the swabbing area.

Legacy Acceptance Criteria (Fallback)

In the absence of sufficient toxicological data or PDE/ADE values, legacy acceptance limits may be temporarily applied as a fallback. These are typically:

• Maximum 10 ppm (10 μg/g) residue on cleaned surfaces.
• Residues less than 1/1000 of the minimum therapeutic dose of the next product manufactured.

It should be emphasized that legacy criteria are less scientifically rigorous and are recommended only until PDE/ADE data are available.

Detergent Residue Rationale and Limits

Detergent residues can pose risks of product contamination and may alter organoleptic properties or stability. The selection of acceptance criteria for detergent residues shall be based on the analytical method used, the toxicological profile, and functional impact. Total Organic Carbon (TOC) analysis is a commonly employed method for detergent residue monitoring given its robustness and universality for organic contaminants.

The detergent evaluation shall be tied to an analytical method validated for specificity, precision, and sensitivity to ensure the limits are meaningful and actionable.

Deviations and Corrective Actions (CAPA)

Should any analytical results from the Sampling Plan defined in Part B exceed established acceptance criteria, a systematic deviation investigation shall be initiated. The investigation protocol must include:

1. Immediate containment of the impacted product and associated batches.
2. Root cause analysis considering process parameters, cleaning procedure adherence, sampling and analytical errors.
3. Re-sampling and re-analysis to verify the initial deviation result.
4. Review of cleaning procedure controls, including detergent preparation, contact time, and rinsing steps.
5. Implementation of corrective and preventive actions (CAPA) such as staff retraining, procedural amendments, or equipment maintenance.
6. Documentation of all investigations, outcomes, and CAPA measures in line with cGMP requirements for traceability and transparency.

Deviations with critical impact on product safety or manufacturing compliance must trigger management review and potentially halt production until resolved.

Continued Verification Plan

Cleaning validation is not a one-time activity but requires ongoing verification to maintain process control and compliance over the product lifecycle. The continued verification plan shall include:

• Periodic sampling of dispensing booth product contact surfaces based on a risk assessment (e.g., quarterly or semi-annually).
• Routine monitoring of cleaning efficacy using the established analytical methods and predefined acceptance criteria.
• Trend analysis of residue data to identify any drift or recurring issues.
• Scheduled equipment inspections for surface integrity and cleaning accessibility.
• Review and update of cleaning procedures and acceptance criteria as new products, detergents, or production methods are introduced.

Verification efforts should be documented and incorporated into the site’s quality management system reviews.

Revalidation Triggers

Revalidation of the dispensing booth cleaning process shall be performed whenever significant changes occur that may impact cleaning efficacy. Common triggers include but are not limited to:

• Introduction of a new product, especially with different physical or chemical properties.
• Change in detergent formulation or supplier.
• Modification to cleaning procedures, such as contact time, temperature, or equipment parts.
• Maintenance or replacement of key dispensing booth components impacting contact surfaces.
• Any deviations or out-of-specification cleaning validation results.
• Regulatory updates or internal audit findings necessitating renewed validation.

Revalidation scope should be commensurate with the change impact and based on established risk management principles.

Annexures and Templates

The following annexures and templates are integral to the dispensing booth cleaning validation package, facilitating documentation and ensuring procedural consistency:

Site-specific inputs required for template completion include:

• [detergent_name]
• [rinse_volume_L]
• [swab_area_cm2]
• [PDE_API_mg_per_day]
• [Batch_Size_kg]
• [Max_Daily_Dose_mg]
• [Surface_Area_cm2]
• [TOC_Threshold_ppm]
• [Assay_Limit_μg/cm²]
• [Conductivity_Limit_μS/cm]

Conclusion

This cleaning validation protocol for dispensing booth product contact surfaces integrates scientifically robust acceptance criteria based on PDE/ADE-derived MACO methodology, underpinned by sound analytical method validation principles including recovery, LOD, and LOQ performance metrics. The approach ensures justified and measurable residue limits that safeguard patient safety while supporting efficient cleaning processes.

Detergent residue acceptance criteria are tied directly to validated detection methods to prevent residual contamination risks. Strict deviation management and CAPA procedures fortify the quality system’s responsiveness to any out-of-specification scenarios.

Furthermore, continued verification and clearly defined revalidation triggers uphold long-term assurance of cleaning efficacy, responsive to changes in manufacturing conditions or regulatory expectations.

By adhering to these comprehensive justification and governance elements, the dispensing booth cleaning validation will meet regulatory standards and industry best practices, ensuring ongoing compliance and product integrity in oral solid dosage pharmaceutical manufacturing.