Cleaning Validation Protocol and Procedure for Eye Drop Filling Machine Product Contact Parts

Purpose and Scope

This document establishes the cleaning validation protocol and detailed cleaning procedure for the product contact parts of the eye drop filling machine used in the manufacture of ophthalmic dosage forms. The primary objective is to demonstrate that residues from drug products, cleaning agents, and microbial contaminants can be effectively removed to predetermined levels, ensuring patient safety and product quality.

This protocol applies specifically to all equipment components that are in direct contact with the product during filling operations, including but not limited to filling nozzles, manifolds, tubing, and associated seals and gaskets. The validation process covers the cleaning agents, cleaning procedures, sampling methods, analytical techniques, and acceptance criteria required to verify cleaning effectiveness.

The scope includes:

• Cleaning process development and standard operating procedures (SOPs) for the eye drop filling machine product contact parts.
• Validation of cleaning methods aimed at removing active pharmaceutical ingredients (API), formulation residues, and detergent residues.
• Identification and documentation of equipment components requiring validation.
• Definition of acceptance criteria based primarily on Toxicological/Acceptable Daily Exposure (ADE) and Maximum Allowable Carryover (MACO) principles for residue limits.
• Responsibilities for implementation and monitoring of cleaning procedures.
• Health and safety considerations for operators performing cleaning and validation.

Definitions and Abbreviations

Responsibilities

Quality Assurance (QA): Review and approve the cleaning validation protocols, procedures, and final validation reports. Ensure compliance with regulatory standards and oversee deviation management.

Quality Control (QC): Conduct sampling, analytical testing for residue and microbial contamination, and report results against acceptance criteria.

Validation Team: Design and execute validation protocols, coordinate equipment qualification, and ensure documentation integrity.

Production/Operations: Execute the cleaning procedure as per SOPs, support sampling activities, and maintain cleaning records.

Engineering/Maintenance: Support equipment disassembly/reassembly procedures, preventive maintenance, and troubleshooting of cleaning system components.

Safety and Personal Protective Equipment (PPE)

• Operators must wear appropriate PPE based on risk assessment, including but not limited to gloves, eye protection, lab coats, and masks to prevent contamination or exposure during cleaning activities.
• Follow Material Safety Data Sheets (MSDS) for all cleaning agents, detergents, and disinfectants used, paying attention to hazards such as skin irritation, respiratory risk, or chemical burns.
• Ensure adequate ventilation is maintained in cleaning and sampling areas to reduce inhalation risks.
• Training on safe handling and spill response procedures is required before initiating cleaning tasks.
• Use lockout/tagout procedures as necessary to ensure equipment cannot start unexpectedly during cleaning.

Equipment Overview and Product Contact Parts

The eye drop filling machine comprises multiple key components with product contact surfaces requiring validated cleaning:

All parts are designed to be dismantled as needed for cleaning access. Cleaning validation addresses both in situ cleaning and component removal where applicable.

Cleaning Strategy Overview

The overall cleaning approach follows a risk-based and science-driven strategy focused on removing drug product residues, cleaning agents, and microbial contaminants from product contact parts. This strategy encompasses:

• Application of validated cleaning agents compatible with materials of construction and capable of solubilizing or removing formulation residues and detergents.
• Sequential cleaning steps including pre-rinse with purified water, detergent wash, rinse(s) with purified water, and optional sanitization/disinfection based on microbial risk assessment.
• Use of both manual and automated cleaning processes as appropriate for complex geometries.
• Validated sampling plan selecting critical product contact points for residue verification.
• Analytical methods to quantify API residues, cleaning agent residues (through TOC or conductivity), and microbial bioburden where applicable.
• Defined hold times for dirty and cleaned states to ensure residue does not degrade or harden, impacting cleanability.
• Documentation of cleaning conditions, including temperatures, volumes, contact times, and detergent concentrations.

Cleaning Agents and Tools

Tools used during cleaning include:

• Swabs and sponges compliant with pharmaceutical cleaning validation.
• Spray nozzles and pressure washers with validated configurations.
• Brushes with synthetic fibers approved for GMP use to manually access critical product contact zones.
• Sampling materials such as sterile swabs and rinses for analytical testing.

Hold Times Definitions

Site-specific determination of these hold times is critical based on formulation composition, ambient conditions, and microbial risk.

Records and Forms

Accurate and controlled documentation is essential for regulatory compliance and traceability. The following list identifies records and forms required:

Site-Specific Inputs Required

• Identity and formulation details of APIs and excipients in the product to calculate ADE/PDE.
• Validated analytical methods and detection limits for API and detergent residue.
• Detergent product name, composition, and recommended use concentration.
• Volume of rinse water used in each cleaning stage ([rinse_volume_L]).
• Swabbed surface area for sampling ([swab_area_cm2]).
• Maximum allowable hold times for dirty and clean equipment ([dirty_hold_time_hours], [clean_hold_time_hours]).
• Environmental conditions for cleaning and sampling.
• Microbial risk assessment results to determine if microbial limits apply.
• Batch sizes and maximum daily doses to support MACO calculations.
• Equipment material specifications and surface finish details for cleaning agent compatibility.

Cleaning Procedure

1. Pre-Cleaning Preparation:
   1. Ensure the Eye Drop Filling Machine is in a clean and powered-off state following the end of production.
   2. Wear appropriate PPE (gloves, gown, mask, eye protection) before starting cleaning operations.
   3. Gather all cleaning materials, including [detergent_name], suitable brushes, lint-free cloths, swabs, distilled water, and drying equipment.
   4. Verify availability of necessary documentation forms for recording cleaning parameters and observations.
2. Disassembly of Product Contact Parts:
   1. Refer to the equipment manual for correct disassembly sequence to avoid damage.
   2. Carefully dismantle each product contact component including filling nozzles, valves, tubing segments, and container holders.
   3. Place disassembled parts on a clean, sanitized surface to prevent contamination.
3. Removal of Gross Residues:
   1. Use dry lint-free cloths or disposable wipes to remove visible product residues from all disassembled parts.
   2. For tight areas or crevices, use suitable brushes or cotton swabs wetted with distilled water.
   3. Dispose of waste materials in accordance with site-specific hazardous material procedures.
4. Washing Sequence:
   

   Step	Action	Parameters	Comments
   1	Prepare detergent solution	Detergent: [detergent_name] Concentration: [detergent_concentration] % w/v Temperature: [detergent_temp] °C	Use fresh solution each cleaning cycle
   2	Immerse disassembled parts in detergent solution	Duration: [detergent_immersion_time] minutes Agitation: Gentle manual or mechanical	Ensure complete submersion and contact with detergent
   3	Manual brushing of complex geometries	Brush with appropriate hardness brushes targeting crevices	Focus on filling nozzles, valve seats, and tubing ends
   4	Drain and remove detergent solution	Completion within 5 minutes after brushing	Minimize detergent drying on parts

5. Intermediate Rinse:
   1. Rinse parts with potable water to remove residual detergent and loosened product residues.
   2. Use a minimum rinse volume of [rinse_volume_L] liters per batch.
   3. Inspect rinse water clarity; repeat rinse if turbidity or foam persists.
6. Final Rinse:
   1. Perform a thorough rinse with purified water (or water for injection, as applicable) using fresh [rinse_volume_L] liters.
   2. Ensure all traces of detergent and product residues are removed.
   3. Utilize flowing rinse where possible to enhance removal efficiency.
   4. Confirm rinse water conductivity meets specified limits to indicate absence of detergent residues.
7. Drying:
   1. Dry components using filtered compressed air or lint-free cloths to prevent contamination.
   2. Confirm complete dryness visually and/or by moisture determination techniques.
8. Reassembly:
   1. Reassemble cleaned parts according to equipment-specific instructions.
   2. Verify all connections are secure and aligned to prevent leaks or contamination during operation.
9. Visual Inspection:
   1. Conduct a thorough visual inspection under adequate lighting to ensure absence of residues, discoloration, or damage.
   2. Document observations and escalate discrepancies to QA for evaluation.

Cleaning Parameters Table

Sampling Plan

Sample Collection Procedure

1. Wear powder-free gloves and replace before each sampling location to avoid cross contamination.
2. Use sterile swabs moistened with validated extraction solvent (e.g., 0.1% w/v Tween 80 in purified water or as per validated cleaning method) for sampling.
3. Swab the defined area with uniform pressure in horizontal and vertical strokes.
4. Place swabs immediately into pre-labeled sterile containers with extraction solvent.
5. Seal sample containers and record pertinent information in sampling log including environmental conditions.
6. Maintain chain-of-custody documentation from sampling to laboratory receipt.

Rationale for Sampling Approach

The selected sampling locations target critical product contact surfaces where residues are most likely to persist due to geometry, contact duration, or cleaning accessibility. Multiple swabs per location improve representativeness and reliability of residue detection. Swab area selection of [swab_area_cm2] cm² follows industry guidance to optimize limit of detection and extraction efficiency for surface assays.

Chain-of-custody controls and timely sample handling minimize risk of sample contamination or degradation, ensuring accurate analytical results to support validation and GMP compliance.

Site-specific Inputs Required

• Detergent name and validated concentration ([detergent_name], [detergent_concentration])
• Detergent solution temperature and contact time ([detergent_temp], [detergent_immersion_time])
• Rinse volumes ([rinse_volume_L]) and water quality limits ([pw_conductivity_limit])
• Swab area per location ([swab_area_cm2])
• Sampling solvent composition for swab extraction

Final Rinse

1. Perform final rinsing of all disassembled parts using purified water (WFI or equivalent) to ensure removal of detergent residues.
2. Use a minimum rinse volume of [rinse_volume_L] liters per part, ensuring thorough coverage and flow-through of complex components such as nozzles and tubing.
3. Rinse water temperature should be maintained at [rinse_water_temp] °C to enhance removal efficiency.
4. Drain parts completely to avoid water pooling which may lead to microbial growth.

Drying

1. Dry cleaned parts using filtered compressed air (grade and pressure: [compressed_air_specifications]) directed through internal channels.
2. Alternatively, use lint-free cloths to remove surface moisture from external surfaces.
3. Ensure parts are completely dry before reassembly to prevent microbial proliferation and corrosion.
4. Drying area and equipment must meet cleanliness standards (ISO class [cleanliness_class]).

Reassembly

1. Reassemble the product contact parts following the equipment manual to maintain integrity and functionality.
2. Check seals, O-rings, and gaskets for wear or damage; replace as needed prior to reassembly.
3. Document time and personnel involved in reassembly for traceability.

Cleaning Validation Sampling Plan

Sampling Locations

Sampling should target representative product contact surfaces identified as high-risk residue retention points including:

• Filling nozzles’ internal and external surfaces
• Valve seats and sealing faces
• Inner tubing surfaces exposed to product
• Container holders/contact points that interface with the filled vials

Sampling Methods

1. Swab Sampling: Utilize validated swabbing technique employing pre-moistened swabs with sampling solvent compatible with assay methods. Swabbing area: [swab_area_cm2] cm².
2. Rinse Sampling: For internal passages where swabbing is impractical, perform rinse sampling with specified solvent volume ([rinse_volume_mL] mL) collected and analyzed.

Sampling Frequency

• Initial validation: Samples collected after final rinse and drying following cleaning of the machine after product run.
• Routine monitoring: Periodic sampling per site-established interval based on risk assessment.

Analytical Methods for Residue Determination

Active Pharmaceutical Ingredient (API) Residue Testing

• Utilize a sensitive and validated assay (e.g., HPLC, UV-spectroscopy) specific for the API in the ophthalmic formulation.
• Limit of detection (LOD) and limit of quantification (LOQ) must be established and fit for cleaning validation purposes.

Detergent Residue Testing

• Quantify detergent residues using a validated method such as Total Organic Carbon (TOC), conductivity, or specific surfactant assays where applicable.
• Establish acceptance limits for detergent residues based on toxicological evaluation and method sensitivity.

Microbial Limits (If Applicable)

• Risk assessment to determine necessity of bioburden testing before release post-cleaning.
• Where applicable, microbial limits shall conform to pharmacopeial limits for ophthalmic manufacturing environments (e.g., microbial limits ≤ [microbial_limit_CFUs]/cm²).

Cleaning Validation Acceptance Criteria

Residual API Limit Calculation Using PDE/ADE-Based MACO Methodology

The Maximum Allowable Carryover (MACO) shall be calculated as follows:

The analytical method must be validated to detect residues below the MACO with appropriate safety margins.

Detergent Residue Limits

• Acceptance criteria shall be based on validated method thresholds (e.g., TOC ≤ [TOC_limit_ppm], or conductivity ≤ [conductivity_limit_µS/cm]).
• Established limits must be supported by toxicological assessment and rinse validation.

Legacy Acceptance Criteria (Fallback)

• When PDE/ADE data are unavailable, the traditional limit of ≤10 ppm or 1/1000th of the normal therapeutic dose equivalent may be applied cautiously.
• This approach is considered conservative but lacks contemporary toxicological alignment.

Documentation and Records

• Complete cleaning records shall include cleaning batch number, operator name, date/time, detergent batch and concentration, temperature, rinse volume, drying conditions, and sampling details.
• Analytical results and acceptance criteria evaluation must be documented and formally reviewed by QA/Validation.
• Deviation management procedures shall be initiated if acceptance criteria are not met.
• Retention of cleaning validation documentation shall comply with GMP and regulatory requirements ([document_retention_period]).

Site-Specific Inputs Required

• [detergent_name], [detergent_concentration], [detergent_temp], [detergent_immersion_time]
• [rinse_volume_L], [rinse_water_temp]
• [compressed_air_specifications]
• [swab_area_cm2], [rinse_volume_mL]
• [PDE_or_ADE_mg], [Next_product_max_dose_mg], [Cleaned_product_max_dose_mg]
• [TOC_limit_ppm], [conductivity_limit_µS/cm]
• [microbial_limit_CFUs]
• [document_retention_period]

Recovery, LOD, and LOQ Expectations

For the eye drop filling machine cleaning validation, analytical methods employed for residue estimation must demonstrate adequate recovery, limit of detection (LOD), and limit of quantitation (LOQ) to ensure confidence in the cleaning efficacy evaluation. Recovery studies shall be performed by spiking known quantities of product residue, cleaning agents, and active pharmaceutical ingredients (API) onto representative product contact surfaces (as defined in the Sampling Plan in Part B).

Expected benchmarks for method performance:

All validation results from recovery, LOD, and LOQ studies shall be documented and reviewed prior to protocol approval. Site-specific adjustments for analytical sensitivity should be incorporated based on equipment capabilities and laboratory instrumentation.

Acceptance Criteria Methodology (PDE/ADE MACO Approach)

This protocol adopts the PDE (Permitted Daily Exposure) or ADE (Acceptable Daily Exposure)-based Maximum Allowable Carryover (MACO) methodology for establishing acceptance criteria of residual product and cleaning agents on the eye drop filling machine product contact parts. This approach aligns with regulatory expectations and risk-based residue limits scientifically justified through toxicological assessments.

Methodology Overview:

• PDE/ADE Determination: Toxicological evaluations establish the maximum safe daily intake of residual API or cleaning agent (in mg/day) for patients consuming the next product batch.
• Batch Size Normalization: The PDE/ADE is divided by the mass or volume of the smallest subsequent batch processed on the equipment.
• MACO Calculation: The resulting value defines the maximum allowable carryover per batch after cleaning.
• Surface Area Consideration: The MACO value is scaled to the sampling surface area to set detection limits correlating with swabbing/sampling techniques.

General PDE/ADE MACO Formula:

MACO (mg) = PDE or ADE (mg/day) × Batch Size of subsequent product (units) ÷ Daily maximum dose of subsequent product (units)

Calculating MACO per Sampling Surface Area:

Therefore, the acceptance limit per swab is:

Acceptance Limit (mg/cm²) = MACO / A

Example Calculation Structure (with placeholders):

1. Determine PDE/ADE for residual API or cleaning agent: [PDE/ADE] mg/day
2. Determine smallest batch size for the subsequent product manufactured on the same equipment: [B] units
3. Determine maximum daily dose of that product: [D] units/day
4. Calculate MACO (mg): MACO = ([PDE/ADE] × [B]) ÷ [D]
5. Obtain surface area swabbed: [A] cm²
6. Calculate acceptance limit per sampling point: Acceptance Limit = MACO / [A]

The cleaning validation report should contain all calculations and supporting toxicological documentation demonstrating rationale and compliance.

Legacy Acceptance Criteria (for reference only)

Legacy acceptance limits such as 10 ppm or 1/1000 of the clinical dose may be referenced as fallback criteria if full PDE/ADE data or toxicological support is unavailable. These criteria are less precise and should only be applied when justified with accompanying risk assessment and regulatory consultation.

Detergent Residue Rationale and Acceptance

Detergent residues on product contact surfaces can pose significant risks including contamination, incompatibility with the product, adverse patient reactions, and interference with product stability. The cleaning validation must therefore include detergent residue assessment to ensure removal to negligible levels.

Rationale:

• The detergent chosen ([detergent_name]) should be non-toxic and be approved for use with ophthalmic products.
• Detergent residues should be monitored using validated specific methods such as Total Organic Carbon (TOC), conductivity measurement, or a detergent-specific analytical assay.
• Acceptance limits for detergent residues must be scientifically justified and linked to safety thresholds or technical limits derived from formulation compatibility studies.

Typical Detergent Residue Acceptance Criteria:

Acceptance criteria shall be defined based on the most sensitive and appropriate method to ensure risk mitigation and regulatory compliance.

Deviations and CAPA Management

Any deviations detected during cleaning validation testing—including analytical failures, sample contamination, atypical residue findings, or sampling technique issues—must be thoroughly investigated.

Deviation Handling Procedure:

1. Document the deviation promptly, including nature, impact, and potential risk to product quality.
2. Initiate root cause analysis (RCA) to identify process, training, equipment, or material failures.
3. Implement corrective and preventive actions (CAPA) focused on eliminating recurrence and mitigating associated risks.
4. Reassess cleaning procedure and sampling methods to confirm adequacy post-CAPA implementation.
5. Conduct additional validation runs or sampling as necessary to demonstrate CAPA effectiveness.
6. Review and approve revised documentation to update procedures and validation protocols if applicable.

All deviations, RCA reports, and CAPA effectiveness check documentation must be archived as part of the cleaning validation dossier.

Continued Verification Plan

Ongoing assurance of the cleaning process effectiveness after initial validation is crucial for sustained compliance and product safety. Continued verification includes routine monitoring activities that confirm consistent adherence to validated cleaning parameters.

• Periodic Sampling: Conduct scheduled sampling and testing of product contact surfaces per the Sampling Plan defined in Part B at predetermined intervals (e.g., quarterly or per batch risk assessment).
• Trending and Analysis: Review residue data trends to identify gradual drifts or sudden changes potentially indicating cleaning process deterioration.
• Cleaning Procedure Audits: Perform periodic audits of cleaning operations including operator technique, equipment maintenance, and cleaning agent preparation accuracy.
• Microbial Monitoring (if applicable): Where risk assessment indicates, include microbial contamination surveillance on cleaned surfaces and rinse waters.
• Change Control Integration: Incorporate cleaning process changes, new products, or modification in cleaning agents under validation review prior to implementation.

Continued verification data shall be reviewed by Quality Assurance with documented conclusions regarding process control status and identification of any revalidation needs.

Revalidation Triggers

Cleaning revalidation is required whenever changes or events potentially impacting cleaning effectiveness occur. Key triggers for revalidation include but are not limited to:

• Introduction of a new product or significant formulation change on the eye drop filling machine
• Change of cleaning agent, detergent or disinfectant, especially if a new chemical class
• Modifications to cleaning procedures, equipment design, or process parameters
• Equipment maintenance or repairs affecting product contact surfaces
• Repeated deviations or failures in cleaning verification testing
• Regulatory updates or new guidance mandating enhanced cleaning validation criteria
• Microbial contamination trends or product complaints indicating potential cleaning inadequacy

Revalidation scope and extent must be determined based on risk assessment, incorporating focused sampling and testing aligned with the process changes. Documentation of revalidation justifications, protocols, and outcomes shall be maintained in the validation master plan.

Annexures and Templates

The following annexures and templates shall be referenced alongside this protocol to ensure comprehensive governance and documentation:

Conclusion

The cleaning validation acceptance criteria for the eye drop filling machine product contact parts are rigorously justified using a PDE/ADE-based MACO methodology, ensuring patient safety and regulatory compliance through scientifically derived residue limits. Analytical methods shall demonstrate adequate recovery, sensitivity, and specificity to reliably detect residual product and detergent to levels well below established acceptance limits. Implementation of risk-based detergent residue assessment using validated TOC or specific assays ensures compatibility with ophthalmic product formulations. A robust deviation and CAPA framework supports prompt correction of any cleaning validation anomalies, while a structured continued verification plan guarantees sustained cleaning performance in routine operations. Defined revalidation triggers maintain process control by requiring reassessment following significant changes or adverse trends. With comprehensive documentation references for analytical validation, sampling, and quality governance, this protocol framework facilitates confident, inspection-ready cleaning validation tailored for critical ophthalmic filling equipment.