Stick Packing Machine Product Contact Parts Cleaning Validation Protocol and Procedures

Purpose and Scope

The purpose of this document is to establish a standardized cleaning validation protocol and standard operating procedure (SOP) for the cleaning of product contact parts of stick packing machines used in the manufacturing of pharmaceutical powder dosage forms. This protocol ensures that the cleaning process effectively removes residues of active pharmaceutical ingredients (APIs), excipients, and cleaning agents to meet predefined acceptance criteria, thereby preventing cross-contamination and ensuring patient safety.

This protocol applies to the entire product contact surface area of the stick packing machine utilized in powder stick packaging operations. It covers the validation of cleaning procedures through a risk-based, science-driven approach suitable for regulatory inspection readiness and pharmaceutical Good Manufacturing Practice (GMP) compliance.

The scope includes product contact parts such as filling nozzles, sealing jaws, feed screws, hoppers, and any other surfaces in direct contact with the product during manufacturing.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

Personnel involved in the cleaning and validation activities must adhere to established safety guidelines to prevent occupational hazards. The following PPE must be worn during cleaning operations:

• Chemical-resistant gloves suitable for handling detergents and solvents.
• Protective goggles or face shield to prevent splashes to eyes.
• Laboratory coats or disposable coveralls to protect skin and clothing.
• Closed-toe, non-slip footwear.
• Respiratory protection if recommended by Safety Data Sheets (SDS) of cleaning agents.

All cleaning agents and chemicals must be handled according to their SDS instructions. Adequate ventilation should be ensured in cleaning areas to avoid inhalation of fumes. Emergency wash stations and first aid kits should be accessible near cleaning locations.

Equipment Overview and Product Contact Parts

The stick packing machine subject to cleaning validation includes the following major components with product contact surfaces:

Materials of construction are selected based on corrosion resistance and cleanability. All surfaces exposed to product must be included in the cleaning validation scope.

Cleaning Strategy Overview

The cleaning approach for the stick packing machine focuses on a scientifically justified, risk-based methodology to ensure removal of product residues and cleaning agents within validated limits. The core elements include:

• Pre-cleaning / Dry Cleaning: Removal of gross product residues through vacuuming, brushing, or compressed air blow-off prior to wet cleaning.
• Detergent Cleaning: Use of an optimized detergent ([detergent_name]) concentration and temperature to solubilize or dislodge powder residues.
• Rinsing: Multiple rinse steps with purified water or WFI to remove detergent residues and solubilized product residues.
• Visual Inspection: Verification of absence of visible residue after cleaning steps.
• Sampling and Analytical Verification: Surface swabbing and rinse sampling assessed by validated analytical methods to confirm residue removal within acceptance criteria.
• Cleaning Frequency and Hold Time Management: Defined maximum allowable hold times for uncleaned (dirty) and cleaned equipment to prevent residue hardening or microbial growth.

Cleaning validation will establish robust parameters including detergent concentration, temperature, contact time, and rinse volumes to reliably achieve cleanliness.

Cleaning Agents and Tools List

Hold Times Definitions

Hold times are established based on product characteristics and microbial risk assessment to prevent residue drying, crystallization, or microbial growth.

Records and Forms List

Site-specific Inputs Required

• Name and composition of detergent agent(s) used during cleaning ([detergent_name])
• Typical rinse volumes required for each rinse cycle ([rinse_volume_L])
• Surface area for sampling swabs ([swab_area_cm2]) and swab type
• Defined dirty hold time prior to cleaning ([dirty_hold_time_hours])
• Defined clean hold time after cleaning ([clean_hold_time_hours])
• Specific analytical methods implemented for detergent residue and product residue (e.g., TOC, HPLC, conductivity)
• Critical cleaning steps and parameters per site equipment configuration
• Risk factors related to microbial contamination (if microbial limits apply)

Stick Packing Machine Cleaning Procedure

1. Pre-Clean Preparation
   1. Ensure the stick packing machine is in a stopped and safe state following production completion.
   2. Don appropriate personal protective equipment (PPE) including gloves, gown, and eye protection.
   3. Record production batch number, product ID, and cleaning event details in the cleaning log.
   4. Isolate the machine area to prevent cross-contamination or unauthorized access.
   5. Verify availability and suitability of cleaning agents, rinsing water, and cleaning tools prior to start.
2. Disassembly of Product Contact Parts
   1. Refer to the manufacturer’s disassembly guide to dismantle the following product contact parts:
      • Product feed hoppers
      • Filling nozzles
      • Sealing jaws and bars
      • Conveyors in contact with powder
      • Feed screws or augers
   2. Place parts on designated cleaned and sanitized surfaces to avoid contamination.
   3. Document part numbers, condition, and note any abnormalities or damage observed.
3. Pre-Rinse
   1. Using potable water at [water_temperature_°C], pre-rinse disassembled parts and machine surfaces to remove residual product.
   2. Ensure rinsing is done to remove loose powder; volume used per part should not be less than [rinse_volume_L].
   3. Collect rinse water from final drain point for conductivity or TOC baseline measurement, if applicable.
4. Washing
   1. Prepare wash solution with [detergent_name] at concentration of [detergent_concentration_%] in water at [wash_temperature_°C].
   2. Use mechanical or manual cleaning methods:
      • Manual: Apply with brushes and cloths dedicated for this cleaning cycle.
      • Mechanical: Circulate detergent solution through the product contact parts if designed for CIP.
   3. Clean all disassembled parts thoroughly, ensuring all crevices, threads, and hard-to-reach areas are addressed.
   4. Contact time for detergent should be at least [contact_time_minutes] to ensure adequate soil removal.
   5. Document detergent batch number and concentration verification result.
5. Rinsing After Washing
   1. Rinse all cleaned parts and machine surfaces with potable water, using a minimum volume of [rinse_volume_L].
   2. Perform multiple rinsing cycles as necessary to reduce detergent residue below detection levels.
   3. Collect rinse water samples post-final rinse for conductivity or TOC confirmation as per protocol.
6. Drying
   1. Dry all product contact parts using clean, filtered compressed air or lint-free towels.
   2. Ensure parts are completely dry before reassembly to prevent microbial growth or corrosion.
7. Reassembly
   1. Follow manufacturer’s instructions to reassemble the product contact parts.
   2. Check for correct fitting and ensure all fasteners and seals are secure.
   3. Verify function/movement of parts following reassembly.
8. Visual Inspection
   1. Perform a detailed visual inspection under appropriate lighting conditions of all product contact surfaces.
   2. Ensure no visible residues, stains, or debris remain.
   3. Document inspection results and note any deviations for immediate investigation and corrective action.

Cleaning Parameters Table

Sampling Plan for Cleaning Validation

Additional Sampling Protocol Details

1. Swabbing Technique: Use sterile, single-use swabs moistened with an appropriate extraction and neutralization solvent validated to recover residues of the product and detergent. Apply swabbing with firm, overlapping strokes in two perpendicular directions to maximize recovery.
2. Sample Labeling: Every sample container must be labeled with a unique identifier including production batch, sampling location code, date and time of collection, and initials of the person performing sampling to maintain integrity.
3. Chain-of-Custody: Maintain documented chain-of-custody for all collected samples from collection, transportation, and receipt in the analytical laboratory. Ensure samples are kept secure and inaccessible to unauthorized personnel.
4. Sample Handling and Storage: Samples shall be transported under controlled temperature conditions to the laboratory within [max_transport_time_hours]. Store at 2°C to 8°C if analysis is not immediate to prevent degradation or microbial growth.
5. Sample Quantity: Collect sufficient number of samples per location to permit replicate analysis and confirm method robustness, typically two swabs composited or separate as described in the sampling table.
6. Documentation: Complete sampling forms capturing environmental conditions, deviations, observed cleanliness, and any anomalies during sampling.

Site-Specific Inputs Required

• [detergent_name]: Name and specification of cleaning agent used.
• [rinse_volume_L]: Exact volume of rinse water per cleaning step.
• [swab_area_cm2]: Defined sampling surface areas for swabs.
• [pre_rinse_temp_°C]: Target temperature for pre-rinse water.
• [detergent_concentration_%]: Concentration of detergent for washing solution.
• [wash_temperature_°C]: Temperature for washing solution.
• [contact_time_minutes]: Minimum detergent contact time during washing.
• [max_transport_time_hours]: Maximum permissible time to reach laboratory.

Analytical Method Validation: Recovery, LOD, and LOQ Expectations

Accurate analytical quantification is vital for validated cleaning procedures, ensuring product safety and compliance in stick packing machine cleaning validation. The validation of analytical methods used for residue detection must encompass Recovery, Limit of Detection (LOD), and Limit of Quantitation (LOQ) parameters with rigorous control.

Method validation data should be generated during method development with matrix-matched samples representative of stick packing machine product contact materials. Method robustness against potential interferences such as product excipients or cleaning agents must also be demonstrated.

Acceptance Criteria Methodology: PDE/ADE-Based MACO Approach

The proposed acceptance criteria follow the PDE/ADE (Permitted Daily Exposure/Acceptable Daily Exposure) paradigm integrated with the Maximum Allowable Carryover (MACO) calculation, which ensures scientifically justified and risk-based limits for residue acceptance.

Basic MACO Calculation Structure:

1. Identify PDE/ADE for product ingredients: Determine relevant PDE/ADE values from toxicological or pharmacological data sources for active pharmaceutical ingredients (APIs) and excipients where applicable.
2. Calculate MACO per product component:
   MACO (mg) = PDE or ADE (mg/day) × batch size of next product (kg) / batch size of current product (kg)
3. Calculate residue limit per sample area:
   Residual acceptance limit (mg/cm²) = MACO (mg) / total defined sampling surface area (cm²)
4. Establish analytical acceptance thresholds:
   Set method quantitation limits (LOQ) ≤ residual acceptance limit to ensure detection capability below maximum acceptable carryover.

Site-specific inputs required:

• PDE/ADE values for all ingredient(s) in the product.
• Batch sizes for previous and subsequent products processed on the stick packing machine.
• Sampling surface area ([swab_area_cm2]) based on the machine’s product contact parts.

Example Placeholder Calculation:

Assuming:

• PDE = [PDE_value] mg/day
• Current product batch size = [batch_size_current_kg] kg
• Next product batch size = [batch_size_next_kg] kg
• Sampling area = [swab_area_cm2] cm²

Then,

MACO = PDE × batch_size_next / batch_size_current

Acceptance limit per cm² = MACO / swab_area_cm2

This methodology provides a scientifically justified, patient safety-based acceptance criterion, superior to legacy rules.

Legacy Acceptance Criteria (For Reference Only)

Where PDE/ADE or toxicological data is unavailable, legacy limits such as 10 ppm (parts per million) or 1/1000th of the therapeutic daily dose may be applied as a fallback. These criteria are broadly conservative but may not reflect true safety margins or risk associated with residue carryover.

Detergent Residue Acceptance Criteria and Justification

Detergent residues pose a critical risk of cross-contamination and quality compromise if not adequately controlled. Acceptance limits must be based on the analytical method used for residue quantification and linked to safety or cleanliness benchmarks.

Analytical Methods Commonly Utilized:

• Total Organic Carbon (TOC) analysis: A universal approach useful for quantifying organic residues including detergents. Typically, acceptance limits are expressed in ppm or µg/cm², correlated with patient safety and cleaning efficacy.
• Conductivity measurement: Suited for aqueous detergent formulations; acceptance limits are set considering detergent ion concentration and method sensitivity.
• Specific assay (e.g., colorimetric or chromatographic methods): Targeted detection of detergent components, providing higher specificity for residue confirmation.

Justification:

• TOC measures total organic residues to ensure comprehensive detection of detergent-related organic matter.
• Acceptance limits should not exceed values where toxicological or organoleptic issues may arise; typically aligned with safety thresholds and user tolerance levels.
• Analytical method selection is based on detergent chemistry, site capability, and validation feasibility.
• Integration into overall cleaning validation ensures detergents do not contribute to residue above MACO or PDE-derived limits.

Example acceptance limit: [detergent_name] TOC ≤ [limit_value] ppm corresponding to maximum safe carryover levels, determined through validation studies.

Deviations and Corrective and Preventive Actions (CAPA)

Effective management of deviations during sampling, analysis, or cleaning procedure implementation is essential for ensuring validated cleaning processes remain compliant and effective:

All deviations and CAPAs must be documented, reviewed by Quality Assurance, and trended to support continuous improvement.

Continued Verification Plan

To maintain ongoing assurance of cleaning effectiveness for product contact parts on the stick packing machine, a risk-based continued verification schedule must be established. This plan ensures cleaning validation remains current and reliable.

• Periodic Sampling and Analysis: Scheduled residue testing (e.g., quarterly or per batch frequency aligned with risk) of critical residues, including APIs and detergents.
• Trending of Results: Analyze trends from acceptance data for detecting drifts or emerging issues in cleaning performance.
• Process Monitoring: Routine audits of cleaning procedures, equipment maintenance records, and operator training currency.
• Change Control: Incorporate verification on cleaning effectiveness when cleaning agents, formulations, batch sizes, or equipment configurations change.
• Revalidation Triggers: Continued verification outcomes will identify when revalidation is required.

Site-specific continued verification frequency should reflect product risk, cleaning complexity, and past validation history.

Revalidation Triggers

The stick packing machine cleaning process must undergo revalidation under defined conditions indicating potential degradation of validated cleaning performance. Common revalidation triggers include:

• Changes in formulation, especially new active ingredients or excipients.
• Modification in cleaning agents, detergents, or cleaning process parameters.
• Equipment modification affecting product contact parts or cleaning access.
• Identification of repeated out-of-specification cleaning validation results or CAPA indicating systemic issues.
• Regulatory inspection observations or internal audit findings requiring remediation.
• Prolonged periods without cleaning validation activity or changes in production volume impacting cleanliness.

Each trigger requires a documented risk assessment and a defined revalidation protocol commensurate with the identified impact.

Annexures and Templates

To facilitate consistent and compliant cleaning validation, the following annexures and templates should be appended to this protocol for standardized documentation and execution:

• Annexure A: Sample Calculation Worksheet for PDE/ADE-Based MACO Limits.
• Annexure B: Analytical Method Validation Summary Template (including recovery, LOD, LOQ results).
• Annexure C: Cleaning Validation Sampling Log Template for Stick Packing Machine Surfaces.
• Annexure D: Cleaning Procedure (SOP-style) Checklist and Verification Form.
• Annexure E: Deviations and CAPA Reporting Template specific to cleaning operations.
• Annexure F: Continued Verification Schedule and Record Template.
• Annexure G: Revalidation Risk Assessment and Approval Form.

Conclusion

This cleaning validation protocol’s acceptance criteria leverage a scientifically robust, patient safety-driven PDE/ADE-based MACO methodology, ensuring residue limits for the stick packing machine’s product contact parts are justified and reflective of risk. Analytical methods utilized must demonstrate stringent recovery, sensitivity, and quantitation limits to reliably detect residual API, excipient, and detergent residues within acceptance criteria. Detergent residue acceptance appropriately depends on method selection and toxin profile considerations, governed by validated TOC, conductivity, or specific assays.

Deviations and CAPA processes are critical controls for maintaining compliance and continuous improvement of cleaning procedures. Comprehensive continued verification strategies aligned with product risk profiles minimize contamination risks over processing lifecycles. Clearly defined revalidation triggers preserve validation integrity when changes or data trends indicate potential impacts on cleaning efficacy.

The inclusion of detailed annexures and standardized templates supports training, documentation, and audit readiness, facilitating the validation lifecycle management of cleaning in pharmaceutical powder stick packaging operations.