Cleaning Validation Protocol and SOP for Dropper Filling Machine Product Contact Parts in Pharmaceutical Liquid Oral Dosage Manufacturing

Purpose and Scope

This document establishes the cleaning validation protocol and standardized cleaning procedure for the product contact parts of the dropper filling machine utilized in the manufacture of pharmaceutical liquid oral dosage forms. The intent is to ensure that residues of the product, cleaning agents, and potential microbial contaminants are effectively removed to levels compliant with regulatory and quality standards.

The scope encompasses validation activities directed at the critical contact surfaces of the dropper filling machine, including all parts in direct contact with the formulation during the filling operation. This protocol applies to the cleaning processes following production batches of all liquid oral products filled using this equipment within the manufacturing facility.

The cleaning validation herein aligns with Good Manufacturing Practices (GMP) requirements, industry best practices, and regulatory expectations for cross-contamination control and product safety.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

Cleaning operations on dropper filling machines include exposure to chemical detergents, sanitizers, and physical handling of equipment parts. Personnel involved must adhere to established safety guidelines to minimize risk of harm.

• Mandatory PPE includes chemical-resistant gloves, safety goggles, lab coat or coveralls, and face masks where aerosolization is possible.
• Respiratory protection may be required if handling volatile or strong cleaning agents; refer to the Safety Data Sheets (SDS) for specific chemicals used.
• Ensure proper ventilation in cleaning areas.
• Follow emergency procedures for spills, exposures, or incidents promptly.
• Train employees in safe handling of cleaning chemicals and proper waste disposal.

Equipment Overview and Identification of Product Contact Parts

The dropper filling machine used in liquid oral pharmaceutical production consists of various parts in direct contact with the product. Understanding these parts is essential for effective cleaning process design and validation.

Only parts designated as product contact must be validated to ensure absence of residues post-cleaning. Non-product contact parts may be cleaned per routine maintenance procedures.

Cleaning Strategy Overview

The cleaning approach for the dropper filling machine product contact parts incorporates a validated multi-step process designed to remove product residues, prevent microbial contamination, and eliminate detergent residues to safe levels. The cleaning strategy is risk-based, addressing worst-case residues and incorporating both manual and automated cleaning elements as appropriate.

The high-level cleaning process consists of:

1. Disassembly of product-contact parts where feasible to allow access to internal surfaces.
2. Rinsing to remove gross residues using purified water at adequate rinse volumes ([rinse_volume_L]).
3. Cleaning with validated detergent ([detergent_name]) under controlled parameters including temperature, contact time, and mechanical action.
4. Secondary rinsing with purified water to remove detergent residues and byproducts.
5. Visual inspection of cleaned parts to ensure absence of visible residue.
6. Drying and reassembly under controlled conditions.

The cleaning process parameters are established through preliminary development studies and form the basis of this validation.

Cleaning Agents and Tools

Hold Time Definitions

Records and Forms

The following controlled documents are maintained to ensure traceability, accountability, and compliance:

• Cleaning Validation Protocol – defines the approach, procedures, and acceptance criteria for cleaning validation.
• Cleaning Procedure SOP – detailed stepwise cleaning instructions.
• Cleaning Batch Records – documentation of cleaning execution with parameters and observations.
• Sampling Records – documentation of swab and rinse sample collection including locations and times.
• Analytical Test Reports – results of residue testing including TOC, specific assays, and microbial testing if applicable.
• Deviation and CAPA Records – documentation of any cleaning deviations and corrective/preventive actions taken.
• Training Records – records of personnel training for cleaning and validation activities.

Site-specific Inputs Required

• Validated detergent name and concentration ([detergent_name]).
• Rinse volume per rinse step ([rinse_volume_L]).
• Swab sampling surface area(s) in cm² ([swab_area_cm2]).
• Validated maximum dirty hold time ([dirty_hold_time_hours]).
• Validated maximum clean hold time ([clean_hold_time_hours]).
• Product-specific PDE or ADE values to establish MACO.
• Analytical methods employed (e.g., TOC method details, assay specifics).
• Exact materials of construction of all product contact parts.
• Instrument calibration status and documentation for testing equipment.

Cleaning Procedure for Dropper Filling Machine (Product Contact Parts)

1. Pre-Cleaning Preparation
   1. Ensure the filling machine is switched off and locked out according to SOP to prevent accidental operation.
   2. Wear appropriate personal protective equipment (PPE) including gloves, goggles, and protective clothing.
   3. Remove all bulk residual product from the machine surfaces using clean disposable wipes or lint-free cloths saturated with potable water.
   4. Record pre-clean observations including the type and extent of residue present.
2. Disassembly of Product Contact Parts
   1. Carefully disassemble the product contact parts of the dropper filling machine following the manufacturer’s instructions.
   2. Place dismantled parts on a clean, sanitized surface to prevent environmental contamination.
   3. Inspect all parts for damage or wear and document findings.
3. Manual Washing Sequence
   1. Prepare cleaning solution using [detergent_name] at the manufacturer recommended concentration and temperature, ensuring complete dissolution.
   2. Immerse disassembled parts fully into the cleaning solution.
   3. Brush and scrub all accessible surfaces, paying particular attention to crevices, threads, seals, and small orifices.
   4. Maintain the cleaning contact time at minimum [contact_time_minutes] minutes as per detergent validation data.
   5. Change detergent solution if visibly soiled or after [maximum_use_time_minutes].
4. Mechanical Cleaning (if applicable)
   1. Place the product contact parts in a validated automatic washer, ensuring proper loading to avoid cross-contamination and allow thorough cleaning.
   2. Set washer parameters to validated cycle including detergent dosage, water temperature, and duration ([detergent_dose_ml/L], [temperature_°C], [duration_minutes]).
   3. Run the cleaning cycle and verify completion before unloading.
5. Rinsing Procedure
   1. Rinse all parts with purified water or water-for-injection (WFI) at a flow rate and volume sufficient to remove detergent and cleaning residues ([rinse_volume_L]).
   2. Perform at least two successive rinses; the first to remove bulk detergent; the second to ensure minimal detergent residue remains.
   3. Collect rinse-off samples (if applicable) for detergent residue analysis.
6. Drying of Parts
   1. Dry cleaned parts using a validated method such as filtered compressed air or hot air oven at [drying_temperature_°C] for [drying_time_minutes].
   2. Ensure the drying environment is controlled to prevent particulate or microbiological contamination.
   3. Confirm visually that all moisture is removed.
7. Reassembly of Product Contact Parts
   1. Reassemble the product contact parts carefully, ensuring correct fit and alignment to manufacturer’s specifications.
   2. Document any replacement of worn or damaged parts.
   3. Perform final machine checks for correct operation before return to service.
8. Visual Inspection
   1. Conduct a detailed visual examination under appropriate lighting to ensure absence of visible soil, residue, and moisture.
   2. Use magnification tools if necessary for hard-to-inspect areas.
   3. Record inspection results and any deviations with photographic evidence where feasible.

Cleaning Parameters Table

Sampling Plan for Cleaning Validation

Sampling Locations and Rationale

Sample Labeling and Chain of Custody

1. Each swab/rinse sample is to be labeled immediately upon collection with unique sample ID, date, time, machine ID, and sampler’s signature or initials.
2. Use tamper-evident seal on sample containers.
3. Maintain a chain of custody log documenting sample movement, handlers, and storage conditions.
4. All samples must be transferred to the designated Quality Control laboratory under controlled environment within [max_transport_time_hours].
5. Store samples pending analysis at [storage_temperature] to maintain integrity.

Sample Handling and Preparation

1. Swab samples shall be extracted into validated solvent or buffer as per analytical method requirements within [max_extraction_time_minutes] after sampling.
2. Rinse samples should be collected into pre-cleaned, inert containers ensuring no contamination or absorption occurs.
3. Label all sample extracts clearly and store as per stability data prior to testing.
4. Follow validated procedures for sample preparation, including filtration or dilution if required by analytical methods.
5. Maintain sample tracking in laboratory information management system (LIMS) or equivalent documentation.

Site-Specific Inputs Required

• Name and concentration of detergent used ([detergent_name], [concentration_%])
• Cleaning solution temperature and contact time ([temperature_°C], [contact_time_minutes])
• Rinse volumes and water quality ([rinse_volume_L], purified water or WFI)
• Swab surface area per sampling location ([swab_area_cm2])
• Drying method, temperature, and duration ([drying_temperature_°C], [drying_time_minutes])
• Maximum allowable sample transport and holding times ([max_transport_time_hours], [max_extraction_time_minutes])

Inspection and Post-Cleaning Verification

1. Visually inspect all cleaned parts under adequate lighting and magnification to ensure no visible residues or deposits remain on product contact surfaces.
2. Document visual inspection results and photograph critical surfaces as per site-specific documentation requirements.
3. Ensure parts are free from damage or deformation that could harbor residues or impact functionality.

Cleaning Validation Sampling Plan

Sampling Method

1. Identify sampling locations based on risk assessment, focusing on hardest-to-clean, smallest internal surfaces, seals, threads, and crevices in product contact parts.
2. Use swab sampling method with validated swabs and solvents to recover residues efficiently from defined areas ([swab_area_cm2]).
3. Include rinse sample collection points after the final rinse cycle as applicable.

Sampling Frequency and Batch Selection

1. Perform cleaning validation on worst-case products defined by formulation, concentration, and color.
2. Execute sampling on three consecutive production lots or as defined by site-specific validation protocols to demonstrate cleaning consistency.
3. Repeat sampling for process or equipment changes impacting cleaning effectiveness.

Analytical Methods for Residue Determination

Product Residue Analysis

1. Use validated HPLC, UV-Vis, or specific assay methods for detecting active pharmaceutical ingredients (APIs) on swab or rinse samples, with method sensitivity below MACO limits.
2. Demonstrate method recovery, specificity, accuracy, and precision for targeted residues.

Detergent Residue Analysis

1. Employ Total Organic Carbon (TOC) analysis or conductivity measurement to quantify residual detergent levels where applicable.
2. Define acceptance limits for detergent residues based on toxicological evaluation and method sensitivity.

Microbial Limits (If Applicable)

1. Conduct microbial bioburden testing on cleaned parts based on risk assessment for non-sterile liquid products.
2. Establish acceptable microbial limits in alignment with pharmacopeial requirements or in-house microbiological specifications.

Acceptance Criteria

Active Pharmaceutical Ingredient (API) Residue Limits

Acceptance criteria shall be established following PDE/ADE-based MACO methodology as detailed below:

1. Determine PDE (Permitted Daily Exposure) or ADE (Acceptable Daily Exposure) for the API from toxicological data.
2. Calculate MACO (Maximum Allowable Carryover) using the formula:
   MACO (mg) = (PDE or ADE × Batch Size of Next Product in kg) / Maximum Daily Dose of Previous Product (mg)
3. Convert the MACO value into surface residue limit based on the total surface area of product contact parts.
4. Set analytical method detection limits to reliably quantify residues below MACO.

Placeholder Values Required: PDE/ADE of product [PDE_mg], batch size [batch_size_kg], maximum daily dose [max_dose_mg], total contact surface area [surface_area_cm2].

Detergent Residue Limits

Detergent residues must comply with limits justified by the analytical method used (TOC, conductivity, or specific assay) and toxicological evaluation, typically expressed as mg/cm² or ppm. Limits should be set below sensory thresholds and safety margins.

Site-specific inputs required: detergent residue limit [detergent_limit_mg/cm2] and corresponding analytical detection limits.

Microbial Acceptance Criteria

If applicable, microbial limits shall comply with either:
– USP microbial limits for oral liquids, or
– Site-specific risk-based assigned bioburden levels.
Documentation must include justification for limits based on process and product risk.

Legacy Acceptance Limits (Fallback Only)

If PDE/ADE-based values are unavailable, legacy acceptance criteria may be considered:
– API residues below 10 ppm relative to product concentration,
– or 1/1000^th of the therapeutic dose per cleaning event.
However, this is not preferred and should be replaced by toxicologically justified limits when possible.

Documentation and Reporting

1. Record all cleaning validation activities, including cleaning procedure adherence, sampling records, analytical results, and inspection data.
2. Complete validation summary report comparing results against acceptance criteria, noting any deviations and corrective actions.
3. Maintain traceability of batches, analytical methods, equipment identification, and personnel involved.

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

To ensure the robustness and reliability of the sampling and analytical methods employed for the dropper filling machine cleaning validation, it is imperative to establish stringent recovery, LOD, and LOQ criteria. Recovery studies must demonstrate that residues can be quantitatively retrieved from the selected sampling surfaces, mimicking actual manufacturing conditions and residue types.

Recovery assessments shall be performed during method validation by spiking known quantities of product and detergent residues within the swab area or rinse volumes defined in the sampling plan and evaluating the percentage recovered following extraction and analysis.

Acceptance Criteria Methodology: PDE/ADE-Based MACO Approach

The acceptance criteria for cleaning validation residues on dropper filling machine product contact parts will be primarily based on the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) to establish the Maximum Allowable Carryover (MACO). This approach integrates toxicological safety thresholds into cleaning acceptance levels for patient safety assurance.

MACO Calculation Framework

The MACO for each product residue is derived from the PDE/ADE values as follows:

MACO Calculation Formula:

MACO (mg/cm2) = [PDE_mg_per_day] × [max_daily_dose_units] / ([batch_size_units] × [contact_surface_area_cm2])

The MACO represents the maximum residual amount allowed per unit surface area of the equipment to prevent cross-contamination risks.

Application of MACO to Cleaning Validation

• Sampling results (swabs or rinses) will be converted to mg/cm² or mg/L basis and compared directly against MACO limits.
• If the residue amount does not exceed the MACO, the equipment cleaning is considered effective and validated.
• Acceptance of residue levels will be subject to analytical method sensitivity, ensuring measured concentrations are above LOQ.

Legacy Limits as Fallback Criteria

In scenarios when PDE/ADE data are incomplete or not available, legacy acceptance criteria such as 10 ppm of product in rinse samples or a 1/1000th dose of product residual on equipment surface may be applied as conservative fallback standards. However, these should only be applied temporarily and replaced with PDE/ADE-based criteria as soon as feasible.

Detergent Residue Justification and Rationale

Detergent residues pose potential contamination risks as well as quality concerns. The cleaning agent, [detergent_name], will be controlled using validated methods tailored to detect residues specific to its chemistry. The rationale for detergent residue acceptance includes:

• Use of analytical methods such as Total Organic Carbon (TOC), conductivity, or specific detergent assays calibrated for [detergent_name].
• TOC or conductivity methods can efficiently detect residual organic or ionic detergent components across the equipment surfaces and rinse waters.
• Specific assay methods (e.g., colorimetric, HPLC) will be applied if TOC/conductivity lack specificity or sensitivity to [detergent_name].
• Detergent limits will be established relative to safety thresholds or method detection limits, with typical acceptance criteria defined as:

Method	Acceptance Limit	Justification
TOC	≤ [TOC_limit] ppm residual carbon in rinse	Ensures removal of organic detergent residues to a safe, near-background level.
Conductivity	≤ [conductivity_limit] µS/cm above rinse water base conductivity	Indicative of ionic detergent removal and rinse water purity.
Specific Detergent Assay	≤ [assay_limit] ppm or µg/cm²	Targeted measure for detergent components with known toxicity or quality impact.

Method validation for detergent residue tests will include determination of specificity, recovery from typical surfaces, LOD/LOQ, precision, and accuracy per regulatory guidelines.

Deviations, Corrective and Preventive Actions (CAPA)

Any deviations from the established cleaning validation sample acceptance criteria or procedural anomalies identified during execution shall be documented and investigated. The CAPA process includes:

1. Deviation Identification: Capture deviations related to sampling, analysis, or cleaning efficacy such as residue exceedances or method failures.
2. Root Cause Analysis: Systematic evaluation to determine underlying causes (e.g., inadequate cleaning method, sampling error, analytical issues).
3. CORRECTIVE ACTIONS: Immediate remedial actions such as repeat cleaning, re-sampling, and re-analysis.
4. PREVENTIVE ACTIONS: Process modifications including SOP updates, retraining of operators, equipment changes, or adjustment of cleaning parameters.
5. Impact Assessment: Evaluate whether previous batches manufactured under the same conditions require review or recall.
6. Documentation: All actions and investigations must be recorded in deviation and CAPA logs, approved by QA/Validation teams.

Continued Verification Plan

Cleaning validation is maintained by a risk-based continued verification plan to ensure ongoing cleaning effectiveness during routine manufacturing. The plan will include:

Revalidation Triggers

Cleaning validation for the dropper filling machine must be revalidated or re-assessed when any of the following conditions occur:

• Product Change: Introduction of new formulations with different physicochemical properties that may impact residue removal.
• Cleaning Agent Change: Modification of detergent type or concentration.
• Equipment Modification: Changes to product contact parts or cleaning system that affect cleaning effectiveness.
• Analytical Method Change: Adoption of new residue detection methods requiring new validation.
• Out-of-Specification Results: Repeated failure to meet acceptance criteria during continued verification.
• Manufacturing Process Change: Alterations impacting cleaning duration, temperature, or equipment cycle.
• Regulatory Update: New industry guidance or standards requiring reassessment.

Upon trigger event identification, a documented revalidation plan must be developed and executed with updated protocols reflecting new inputs and risks.

Annexures and Templates

To support effective implementation and documentation of the dropper filling machine cleaning validation, the following annexures and templates are included:

• Annexure 1: Sampling Plan Template (referenced in Part B)
• Annexure 2: Analytical Method Validation Report Template
• Annexure 3: MACO Calculation Worksheet with PDE/ADE placeholders
• Annexure 4: Cleaning Procedure Compliance Checklist
• Annexure 5: Deviation and CAPA Report Template
• Annexure 6: Continued Verification Schedule and Reporting Format
• Annexure 7: Revalidation Assessment and Approval Form

Site-specific inputs required for completion of worksheets and templates:

• [PDE_mg_per_day]
• [batch_size_units]
• [max_daily_dose_units]
• [contact_surface_area_cm2]
• [detergent_name]
• [TOC_limit]
• [conductivity_limit]
• [assay_limit]
• [rinse_volume_L]
• [swab_area_cm2]

Conclusion

The cleaning validation of the dropper filling machine product contact parts employing a PDE/ADE-based MACO acceptance criteria framework ensures product safety and regulatory compliance through a scientifically justified, risk-based approach. The integration of appropriate recovery and method sensitivity benchmarks establishes analytical confidence, while explicit rationale for detergent residue monitoring maintains overall cleaning integrity. Robust deviation and CAPA management, coupled with a dynamic continued verification and revalidation strategy, form the foundation of sustained cleaning effectiveness in the manufacturing environment. Annexures and procedural templates provide structured guidance to facilitate seamless execution, documentation, and audit readiness, thus empowering pharmaceutical manufacturing professionals to uphold the highest standards of product quality and patient safety.