Cleaning Validation Protocol for Sachet Filling Machine Product Contact Parts in Powder Dosage Manufacturing

Purpose and Scope

The purpose of this cleaning validation protocol is to establish a scientifically justified, inspection-ready approach for validating the cleaning processes applied to the product contact parts of the sachet filling machine used in pharmaceutical powder dosage forms manufacturing. This document defines the methodology, responsibilities, equipment, cleaning agents, and strategy to ensure equipment cleanliness meets predetermined acceptance criteria, minimizing the risk of cross-contamination and ensuring patient safety.

This protocol applies specifically to all cleaning activities related to the sachet filling machine’s product contact surfaces, including components such as the powder hopper, dosing system, filling nozzles, sealing jaws, and conveying elements directly exposed to the powder product. The validation covers manual and automated cleaning procedures, sampling methods, hold times, and documentation requirements consistent with current Good Manufacturing Practices (cGMP) and global regulatory expectations.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

Personnel involved in cleaning and validation of the sachet filling machine product contact parts must observe all applicable health and safety requirements to prevent chemical exposure and physical hazards. Minimum PPE requirements include:

1. Chemical-resistant gloves appropriate for detergent handling
2. Protective gown or coverall
3. Eye protection such as chemical splash goggles
4. Respiratory protection if aerosolized powders or detergents could be inhaled
5. Closed-toed safety footwear
6. Hair and beard covers as per cleanroom protocol

All personnel must complete training on the hazards of cleaning chemicals, emergency procedures, and proper donning/doffing of PPE before participation in cleaning validation activities.

Equipment Overview and Product Contact Parts Identification

The sachet filling machine consists of various components directly contacting powder materials during filling operations. The principal parts requiring cleaning validation include but are not limited to:

All above parts are classified as product contact surfaces. Non-product-contact equipment components (e.g., motors, casings) are excluded from cleaning validation.

Cleaning Strategy Overview

The cleaning strategy for the sachet filling machine product contact parts integrates both preventive and corrective approaches to achieve validated cleanliness. This high-level strategy covers:

• Pre-Clean Activities: Removal of gross residues by mechanical disassembly and dry cleaning methods (e.g., vacuuming, dry wiping) to minimize powder dust.
• Detergent Cleaning: Application of a validated detergent solution ([detergent_name]) selected based on efficacy against the powder formulation residues and compatibility with equipment materials.
• Rinsing: Multiple rinses with purified water to ensure removal of detergent and residual powders, monitored by conductivity and TOC measurements.
• Drying: Drying processes ensuring no residual moisture remains, preventing microbial growth or powder adherence.
• Cleaning Validation Sampling: A comprehensive sampling and analytical verification program to confirm effective cleaning.
• Validated Hold Times: Defined maximum allowable periods between cleaning and subsequent usage to maintain validated cleaning state.
• Continuous Monitoring: Routine verification cleaning checks incorporated into scheduled preventive maintenance to sustain validated performance.

Cleaning Agents and Tools

Hold Times Definitions

Records and Forms

• Cleaning Validation Protocol Document
• Cleaning Procedure (SOP) for Sachet Filling Machine Product Contact Parts
• Cleaning Batch Log Sheets with detailed activities, materials, and personnel signatures
• Cleaning Sampling Plan and Sample Collection Records
• Analytical Test Reports for Residue and Microbial Limits
• Equipment Maintenance and Calibration Records
• PPE Usage and Safety Training Records
• Non-conformance and Deviation Reports if applicable
• Final Cleaning Validation Summary Report

Site-specific Inputs Required

• [detergent_name] – exact detergent formulation and supplier details
• [rinse_volume_L] – volume of rinse water per equipment part or total system
• [dirty_hold_time_hours] – allowable time from production end to cleaning start
• [clean_hold_time_hours] – allowable time from cleaning completion to next use
• [swab_area_cm2] – surface area dimension for residue sampling
• Specific materials of construction confirmation for product contact parts
• Details of CIP systems if applicable
• Analytical methods and validation status (TOC, conductivity, specific assays)
• Microbial risk assessment outcome and applicable limits

Cleaning Procedure for Sachet Filling Machine (Product Contact Parts)

1. Pre-Cleaning Preparation
   1. Ensure the machine is powered off and isolated from energy sources as per lockout/tagout procedures.
   2. Remove all sachet packaging materials and bulk powder from the hopper and feed system.
   3. Verify the prior batch production records to confirm the product and cleaning agents used.
   4. Wear appropriate personal protective equipment (PPE) including gloves, gown, and eye protection.
2. Disassembly
   1. Disassemble all product contact parts of the sachet filling machine, including but not limited to:
   • Hopper components
   • Filling nozzles
   • Conveyors or chutes that contact product
   • Sealing jaws in contact with the powder
   • Any gaskets, seals, or detachable tubing in contact with product
   2. Place disassembled parts on clean and sanitized preparation surfaces.
   3. Inspect components for visible contamination or damage.
3. Cleaning – Wash Step
   1. Prepare the cleaning solution using [detergent_name] at the concentration specified by the manufacturer or site SOP.
   2. For manual cleaning:
      • Submerge all disassembled parts in the cleaning solution.
      • Use soft brushes or cloths to scrub all surfaces, focusing on crevices and hard-to-reach areas.
      • Ensure the entire surface area is exposed to the detergent for at least [contact_time_minutes] minutes.
   3. For automated cleaning (if applicable), load components into the washer and run the validated cleaning cycle using [detergent_name].
4. Rinsing Sequence
   1. Rinse all parts thoroughly with potable or purified water to remove detergent residues.
   2. Apply at least [rinse_volume_L] liters per component, ensuring full coverage and elimination of visible foam or residues.
   3. Repeat rinse cycle if required per SOP or until no visible residues or foam remain.
   4. Final rinse should utilize Water for Injection (WFI) or purified water as per site standards to minimize microbial contamination and residue.
5. Drying
   1. Dry all components using lint-free towels or air-dry systems validated for cleanliness.
   2. Ensure no residual moisture remains on any surface; moisture can promote microbial growth or interfere with product quality.
   3. Use filtered air drying if applicable; ensure air quality is monitored and meets specifications.
6. Reassembly
   1. Reassemble product contact parts strictly following the equipment manufacturer’s guidelines.
   2. Verify all parts are correctly and securely fastened to avoid cross contamination or equipment malfunction.
   3. Check the integrity of gaskets and seals; replace if any defects are found.
7. Visual Inspection
   1. Perform a thorough visual inspection of all product contact parts to confirm cleanliness and dryness.
   2. Ensure there is no visible film, residues, discoloration, or particulate matter on any surface.
   3. Document findings and provide photographic evidence if required by site protocol.

Cleaning Validation Parameters

Sampling Plan for Cleaning Validation

Swab Sampling Methodology

1. Use pre-moistened sterile swabs compatible with analytical methods (e.g., TOC-compatible, non-reactive with detergents).
2. Swab defined areas following a zig-zag pattern horizontally and vertically to maximize residue collection.
3. Use a fresh swab for each surface and site.
4. Place each swab in labeled sterile container immediately after sampling.
5. Complete chain-of-custody forms, including time of sampling, person performing, and equipment details.
6. Transport samples to QC analytical laboratory under controlled conditions as required.

Rinse Water Sampling (if applicable)

1. Collect rinse water samples from final rinse step at discharge port closest to product contact component.
2. Collect minimum [sample_volume_ml] mL of rinse water into sterile containers.
3. Label and document sample details similar to swabs.
4. Analyze for detergent residues and Total Organic Carbon (TOC) as per site validated methods.

Additional Site-Specific Inputs Required

• [detergent_name]: Specify detergent(s) used for cleaning.
• [contact_time_minutes]: Minimum detergent contact time for wash step.
• [rinse_volume_L]: Minimum volume for each rinse cycle per component.
• [swab_area_cm2]: Defined swab area size per sampling location.
• [max_hours]: Maximum permissible time from sampling to analysis initiation.
• [sample_volume_ml]: Volume of rinse water sample to be collected.

Verification of Cleaning Effectiveness

Visual Inspection

1. Inspect all product contact parts under adequate lighting for visible residues, discoloration, or damage.
2. Use magnification tools for detailed examination of crevices and hard-to-reach areas.
3. Document findings with photographic evidence where possible.

Analytical Testing of Residual Product and Cleaning Agents

1. Collect samples as per the sampling plan covering all critical surfaces of the product contact parts.
2. Conduct swab or rinse sampling depending on surface characteristics and validation study design.
3. Analyze samples for residual active pharmaceutical ingredient (API) using validated analytical methods (e.g., HPLC, UV-Vis spectrometry).
4. Determine detergent residues by Total Organic Carbon (TOC) testing or specific detergent assay, aligned with [detergent_name] characteristics.
5. Apply acceptance criteria derived from PDE/ADE-based Maximum Allowable Carryover (MACO) calculations:

Parameter	Calculation Input	Description
Residual Limit (mg)	(PDE or ADE) × batch size of next product	Maximum allowed residue quantity per batch to ensure safety
Surface Area (cm²)	[swab_area_cm2]	Area sampled for residue measurement
MACO (µg/cm²)	Residual Limit ÷ Surface Area	Maximum amount of residue per surface unit to comply with PDE/ADE

6. If analytical limits are not achievable or PDE/ADE data is unavailable, fallback to legacy acceptance criteria such as 10 ppm of drug substance or 1/1000th of the therapeutic dose as interim measures with justification.

Microbiological Controls (Risk-Based)

Assessment of Microbial Contamination Risk

1. Perform risk assessment considering product attributes, cleaning agent efficacy, and environmental conditions.
2. Determine necessity of microbiological testing based on product sterility requirements and historical data.

Microbial Testing Procedures

1. Collect rinse water or swab samples from critical contact surfaces following the sampling plan.
2. Perform microbial enumeration tests compliant with USP Microbial Limits Test or equivalent compendial methods.
3. Apply acceptance criteria aligned with site SOPs and regulatory guidance.

Documentation and Record Keeping

1. Complete cleaning batch records capturing cleaning agent lot numbers, concentrations, solution preparation logs, and contact times.
2. Document disassembly and reassembly activities with personnel initials and timestamps.
3. Record results of visual inspections, analytical testing, and microbiological assays.
4. Maintain all data in a dedicated Cleaning Validation Master File for audit readiness.
5. Compile deviation reports and corrective actions if cleaning acceptance criteria are not met.

Site-specific Inputs Required

• Detergent name, concentration, and contact time ([detergent_name], [contact_time_minutes])
• Rinse volume per component ([rinse_volume_L])
• Surface area sampled for residue analysis ([swab_area_cm2])
• PDE or ADE values for active pharmaceutical ingredients involved
• Analytical methods and detection limits for API and detergent residues
• Microbial acceptance limits if applicable

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

Accurate assessment of residual contaminants on the product contact parts of the sachet filling machine is fundamental to ensure the cleaning validation’s reliability. Method validation must demonstrate acceptable recovery levels, confirming that the analytical procedures effectively retrieve residues from sampling matrices such as swabs or rinse samples.

These parameters must be verified during method validation for each analytical technique employed, such as Total Organic Carbon (TOC), High Performance Liquid Chromatography (HPLC), or conductivity measurement. Recovery studies should simulate realistic residue matrix and surface conditions.

Acceptance Criteria Methodology: PDE/ADE-Based MACO Approach

The acceptance criteria for residual contaminants on sachet filling machine product contact parts are defined through a scientifically rigorous PDE (Permitted Daily Exposure) / ADE (Acceptable Daily Exposure)-based MACO (Maximum Allowable Carryover) calculation. This approach aligns with ICH Q3E and FDA guidance and replaces legacy rules such as the old 10 ppm or 1/1000 dose limits.

MACO Calculation Structure:

1. Determine PDE/ADE values for the active pharmaceutical ingredients and cleaning agents involved from toxicological data or regulatory sources.
2. Calculate MACO using the formula:

3. Convert MACO to acceptable residue limits on equipment surfaces taking into account:

Thus, the acceptance limit per sample can be determined by:

Site-specific inputs required:

• PDE/ADE values for drug substances and cleaning agents
• Batch size
• Maximum daily dose
• Surface area values (total and sampled)
• Recovery percentage from method validation

Example placeholder:

This structured approach ensures safety-based, scientifically justified acceptance limits that account for product toxicity, dosage, and equipment specifics.

Detergent Residue Acceptance Rationalization

Detergent residues represent a distinct critical quality attribute and must be separately assessed. The cleaning agents used on the sachet filling machine are verified for their potential toxicity and carryover risk. The acceptance limit for detergent residues is set based on the sensitivity and specificity of the employed analytical method:

• Total Organic Carbon (TOC): Utilized for general organic detergent residues. Acceptance limit is typically set at [TOC_limit_ppm] mg/L, linked to toxicological assessments or threshold CMC values.
• Conductivity: Applied when detergent components alter ionic strength distinctly; specific conductivity limits correspond to safe residual levels.
• Specific Assay: When detergents include identifiable signature molecules (surfactants, enzymes), a validated targeted assay (e.g., HPLC, UV) with defined LOQ offers precise residue quantification and control.

Analytical method sensitivity (LOD/LOQ) must be below the acceptance limit to ensure meaningful detection. Detergent residue limits are mandated by their chemical nature, toxicity data, and compatibility with process requirements.

Example site inputs required:

• Detergent name and chemical composition
• Analytical method type (TOC/conductivity/specific assay)
• TOC or assay-specific acceptance limits
• Recovery data for detergent sampling

Deviations and Corrective & Preventive Actions (CAPA)

Any out-of-specification (OOS) results or deviation observed during cleaning validation sampling or analytical testing must trigger immediate investigation. The investigation protocol should follow Good Manufacturing Practice (GMP) compliant procedures to:

1. Identify root cause, including equipment design, cleaning parameters, human errors, or analytical faults.
2. Implement appropriate corrective actions to rectify the detected non-conformance (e.g., equipment re-cleaning, adjustment of cleaning time or detergent concentration).
3. Develop preventive actions to mitigate recurrence risks, such as operator retraining, procedural updates, or maintenance enhancements.
4. Document all findings, actions, and verifications systematically in deviation and CAPA reports.
5. Reassess the sampling plan or cleaning procedure if repeated failures occur.

Deviations impacting product quality or regulatory compliance must be communicated promptly to QA and Validation teams for integrated resolution.

Continued Verification Plan

Maintaining cleaning validation status necessitates ongoing monitoring to ensure persistent compliance and process control. The continued verification plan includes:

• Routine Sampling: Periodic swab or rinse sampling of product contact parts per the Sampling Plan defined in Part B, to verify consistent cleaning efficacy.
• Analytical Testing: Regular testing of samples using validated methods with established LOD/LOQ, checking against acceptance criteria.
• Review of Cleaning Data: Trending of cleaning residue levels, detergent residues, and microbial counts (if applicable) to detect any drifts or emerging risks.
• Periodic Reassessment: Scheduled comprehensive revalidation every [site-defined interval, e.g., 3 years], or sooner upon significant changes.
• Change Control: Any process, equipment, detergent formula, or cleaning procedure change must undergo risk assessment to determine need for partial/all cleaning validation reexamination.

Cleaning Revalidation Triggers

Revalidation of the sachet filling machine cleaning process must be conducted under the following conditions:

• Equipment Modification: Changes affecting product contact surfaces such as retrofitting, replacement, or design modifications.
• Change in Cleaning Agents: Introduction of new detergents, changes in detergent concentration, or supply source modifications.
• Change in Manufacturing Process: Different product formulations, increased batch sizes, or changes in process parameters impacting cleaning difficulty.
• Repeated Cleaning Failures: Multiple deviations or OOS from cleaning residue tests triggering corrective actions.
• Periodic Scheduled Revalidation: Based on internal policy or regulatory recommendations (e.g., every 2-3 years).
• Regulatory Requests: Following audits, inspection findings, or regulatory changes.

Revalidation scope and sampling intensity must be risk-assessed accordingly, focusing on impacted areas and cleaning steps.

Annexures and Templates List

The following annexures and templates support documentation, execution, and governance of the sachet filling machine cleaning validation:

Conclusion

This cleaning validation protocol for the sachet filling machine product contact parts establishes a scientifically robust framework integrating toxicological safety thresholds with equipment-specific parameters via the PDE/ADE-based MACO methodology. Detailed method validation benchmarks for recovery, LOD, and LOQ ensure assay reliability and traceability of residual detection. The explicit inclusion of detergent residue limits linked to validated analytical methods safeguards against residual cross-contamination risks. Rigorous deviation management aligned with GMP principles ensures continuous process improvement and compliance. The structured continued verification and revalidation plans provide sustained assurance of cleaning efficacy over the equipment lifecycle, thereby protecting product quality and patient safety.