Vibro Sifter Cleaning Validation Protocol and Acceptance Criteria

Purpose and Scope

This document establishes the cleaning validation protocol for vibro sifters employed in the manufacturing of oral solid dosage forms. The intent is to ensure removal of all product residues, cleaning agents, and potential contaminants to meet established acceptance criteria and regulatory requirements. The protocol addresses identification of critical cleaning parameters, roles and responsibilities, cleaning strategies, equipment contact parts, and limits related to residual active pharmaceutical ingredients (APIs), cross-contamination, and detergents.

The scope covers all vibro sifter units used within the production area for oral solid dosage forms including tablet granules, powders, and other particulate materials. This protocol applies equally to new installations, routine validation following cleaning process development, as well as revalidation after equipment modifications or process changes.

Definitions and Abbreviations

• API: Active Pharmaceutical Ingredient
• Cleaning Validation (CV): Documented evidence that a cleaning process consistently reduces residues to predefined acceptable levels.
• Cross-contamination: Unintended residue transfer between products manufactured using the same equipment.
• Detergent: Cleaning agent used for residue removal, including chemical formulations such as alkaline, acidic, or enzymatic cleaners.
• Equipment Contact Parts: All surfaces of the vibro sifter that come into direct contact with product or cleaning agents.
• MACO: Maximum Allowable Carryover, the maximum amount of residual contaminant allowed after cleaning, based on toxicological and analytical considerations.
• PDE/ADE: Permitted Daily Exposure / Acceptable Daily Exposure, limits used in safety-based risk assessment for residual contamination.
• Rinsate: Sample of the final rinse water used during cleaning to verify residue levels.
• Swab Sampling: Surface sampling technique using a pre-moistened swab to assess residue levels on equipment surfaces.
• TOC: Total Organic Carbon, an analytical method for measuring organic residues including detergent residues.
• Validation Master Plan (VMP): A master document describing validation approach across facilities and equipment.
• WFI: Water for Injection

Responsibilities

• Quality Assurance (QA): Review and approve cleaning validation protocols, acceptance criteria, and final reports. Ensure compliance to regulatory and internal standards.
• Quality Control (QC): Perform sampling (swabs, rinses), conduct analytical testing, document results, and provide data for validation evaluation.
• Production: Execute the cleaning procedure as per SOPs, prepare equipment for cleaning, and assist with sampling where required.
• Validation Team: Develop and maintain cleaning validation protocols, review analytical methods suitability, conduct risk assessments, and compile validation reports.
• Engineering/Maintenance: Ensure equipment cleanliness by facilitating dismantling/reassembly, verify functionality of cleaning utilities (water, CIP systems), and support cleaning technique optimization.
• Environmental Health and Safety (EHS): Provide guidance on PPE and safe handling of cleaning agents and chemicals.

Safety and Personal Protective Equipment (PPE)

Personnel engaged in cleaning activities must adhere to site safety guidelines to prevent exposure to chemical detergents and dust particulates. Appropriate PPE must be worn during all cleaning and sampling steps to comply with GMP and occupational safety regulations.

• Protective gloves resistant to cleaning agents (e.g., chemical-resistant nitrile gloves)
• Safety goggles or face shield
• Protective coveralls or lab coats
• Respiratory protection if dust or aerosol generation is anticipated
• Closed-toe, anti-slip footwear

All cleaning chemicals’ Material Safety Data Sheets (MSDS) must be reviewed prior to use. Spill control and first aid measures must be readily accessible in case of accidental exposure.

Equipment Overview and Product-Contact Parts

The vibro sifter is a primarily mechanical device designed to separate fine particles from coarse granules or powders. It consists of a vibrating screen mesh housed in a metal frame mounted on springs or dampers to facilitate vibration.

Key components making product contact include:

• Screen mesh (stainless steel, typically 316L)
• Top cover/lid (stainless steel)
• Discharge hopper and feed inlet (stainless steel)
• Internal frame and support brackets (product-contact surfaces may vary, generally stainless steel)
• Sealing gaskets at product interfaces (material specification documented)

Non-product-contact surfaces (motors, controllers, external frames) are excluded from cleaning validation but require routine cleaning as part of GMP maintenance.

Material of construction and finishing quality of contact parts must support cleaning and avoid particle entrapment or corrosion.

Cleaning Strategy Overview

For this vibro sifter, a robust cleaning strategy integrates manual disassembly, mechanical cleaning, chemical cleaning, and verification through sampling. The objective is removal of gross product residues, API residues, formulation excipients, and cleaning agents.

Cleaning is performed using a multi-step approach:

• Step 1: Manual removal of gross powder by brushing and vacuuming.
• Step 2: Disassembly of screen mesh and related parts for individual cleaning.
• Step 3: Soaking and cleaning in [detergent_name] solution at specified concentration and temperature.
• Step 4: Thorough rinsing with purified water ([rinse_volume_L] liters minimum) to remove detergent residues.
• Step 5: Drying of parts and reassembly under hygienic conditions.
• Step 6: Sampling using swabs from critical contact points and rinsate samples from final rinse water for analytical testing.

The cleaning process parameters such as detergent concentration, temperature, exposure time, and rinse volumes must be optimized during cleaning validation for effective and reproducible residue removal.

Cleaning Agents and Tools List

The choice of cleaning agents is based on site’s approved qualification list and product formulation properties. Examples include:

• Detergents: [detergent_name] — alkaline or neutral detergent selected for solubilizing API/excipient residues without damaging equipment surfaces.
• Purified Water/WFI: For rinsing post detergent cleaning and removal of water-soluble residues.
• Brushes: Soft nylon brushes suitable for stainless steel surfaces to avoid scratching.
• Vacuum Devices: Industrial HEPA-filtered vacuum to remove dry powder residues before wet cleaning.
• Lint-free Cloths and Swabs: For sampling and wiping as per sampling SOP.
• Cleaning Equipment: Soaking tanks or ultrasonic cleaners (if applicable) for enhanced cleaning efficiency.

Hold Times Definitions

Establishing hold times is critical for maintaining cleaning effectiveness and preventing residue hardening which complicates removal.

• Dirty Hold Time: Maximum time allowed between completion of production batch and start of cleaning procedure. For the vibro sifter, this is set at [dirty_hold_time_hours] hours to prevent product drying and caking.
• Clean Hold Time: Maximum time permitted from completion of cleaning through to equipment use or storage. It must ensure no microbial growth or residue re-deposition. For this equipment, clean hold time is [clean_hold_time_hours] hours/days under controlled storage environment.

Site-specific hold times must be supported by scientific rationale and risk assessment.

Records and Forms

Complete and accurate documentation supports full traceability in cleaning validation activities. Records required include:

• Cleaning Procedure Checklist – documentation of completed cleaning steps and parameters.
• Disassembly/Reassembly Logs – to record part handling and condition.
• Sampling Forms – swab and rinsate collection sheets indicating sampling locations and methods.
• Analytical Test Reports – raw data and final reports from residue testing (HPLC, TOC, conductivity, or other relevant methods).
• Cleaning Validation Protocol – planning document describing validation design, sampling strategy, and acceptance criteria (this document).
• Cleaning Validation Report – summarizing results, deviations, and conclusion on cleaning process effectiveness.
• PPE Usage Log – records compliance with safety requirements during cleaning activities.
• Deviation Forms – used to document any unexpected events or non-conformances detected during cleaning or sampling.

All records must comply with GMP documentation standards including legibility, dates, signatures/initials of responsible personnel, and document control per site Quality Management System.

Cleaning Procedure for Vibro Sifter

Pre-Cleaning Preparation

Before initiating the cleaning process, ensure the following:

• Wear appropriate PPE (gloves, gown, hairnet, mask) as per site GMP requirements.
• Ensure that the equipment is not in operation and has cooled down to safe handling temperature.
• Disconnect the vibro sifter from power supply to prevent accidental start-up during cleaning.
• Prepare cleaning agents and materials: [detergent_name], cleaning brushes, lint-free cloths, swabs for sampling, rinse water (purified or potable depending on procedure).
• Identify and document the batch number of the last product processed for record-keeping.

Disassembly of Vibro Sifter for Cleaning

Disassemble the vibro sifter following these steps to ensure all contact parts are accessible for cleaning:

• Remove the upper and lower sieves carefully and place on a clean sanitized surface.
• Detach any sieving frames and clamps.
• Remove product contact surfaces such as the hopper, feeder pan, and outlet chute if detachable.
• Note any non-detachable components for cleaning in situ.

Step-by-Step Cleaning Procedure

Dry Pre-Cleaning

• Brush or vacuum off residual product from all accessible parts and surfaces without dispersing dust into the environment.
• Document the effectiveness of dry cleaning; ensure no visible product residues remain.

Detergent Wash

Prepare the detergent cleaning solution as per manufacturer’s prescribed concentration using [detergent_name].

• Apply detergent solution using soft brushes or spray nozzles to all wettable product contact surfaces.
• Ensure coverage of crevices, edges, and gasket areas.
• Allow detergent to dwell for the specified contact time.

Rinse Sequence

Rinse all cleaned parts sequentially to remove detergent residues.

• Thoroughly rinse all parts using a spray or dipping method to remove detergent and loosened residues.
• Check the rinse water visually for cloudiness or residue presence; repeat rinse if necessary.
• Drain excess rinse water completely to avoid water spots or microbial growth.

Drying

• Dry parts immediately after rinsing to prevent microbial contamination or corrosion.
• Use clean compressed air (filtered, oil-free) to blow dry hard-to-reach areas.
• Alternatively, use lint-free towels to manually dry external surfaces.
• Ensure parts are completely dry before reassembly.

Reassembly and Visual Inspection

• Reassemble the vibro sifter according to the manufacturer’s instructions.
• Check for correct fitting, secure fastening of clamps, and proper placement of gaskets.
• Conduct visual inspection under good lighting to verify no visible residue, discoloration, or damage.
• Document the completion of cleaning and inspection with signature and date.

Sampling Plan for Cleaning Validation of Vibro Sifter

Sampling Methodology

Sampling after cleaning is critical to confirm the absence of product residues, detergent traces, and microbiological contaminants (if applicable).

• Swab sampling: Applied to specified contact surfaces using validated wet swabbing technique with moistened sterile swabs.
• Rinse sampling: Collection of rinse water samples from the final rinse step to quantify residual detergent levels using TOC or specified assay.
• All sampling locations must encompass representative and worst-case sites prone to residue retention, including hard-to-clean areas and product contact zones.

Swab Sampling Locations and Rationale

Rinse Sampling Plan

• Collect samples of the final rinse water collected after cleaning from the disassembled parts and in-situ rinsed equipment surfaces.
• Sample volume: minimum [sample_volume_mL], stored in sterile, labeled containers.
• Analyze for parameters including Total Organic Carbon (TOC) or specific detergent assay to confirm detergent removal.

Microbiological Sampling (If Applicable)

Conduct risk assessment to determine necessity of microbiological swabbing. If justified, sample surfaces post-cleaning but pre-sterilization for microbial bioburden.

• Sampling locations: same as swab locations for residues.
• Method: contact plates or wet swabbing.
• Acceptance criteria based on predefined microbial limits.

Sampling Procedure and Documentation

• Use individually packed sterile swabs moistened with validated extraction solvent (e.g., purified water or appropriate buffer).
• Swab the defined area using consistent pressure and technique (horizontal + vertical strokes).
• Place swab in sterile tube with extraction solvent; label with sample ID, date, and operator initials.
• Log all samples in the sampling log with sampling time, location, and batch information.
• Transport samples to QC laboratory under controlled conditions (temperature, time) to maintain integrity.

Sample Identification Coding Example

The sample ID should follow logical coding to ensure traceability:

VS – Vibro Sifter
[Location code] – Swab area (e.g., ULS for Upper Lower Sieve)
[Batch_no] – Batch number or cleaning batch ID
[Date] – Sampling date in YYYYMMDD format

Site-Specific Inputs Required

• Detergent name and concentration ([detergent_name], [detergent_concentration])
• Detergent cleaning temperature ([cleaning_temperature])
• Contact time for detergent wash ([contact_time])
• Rinse volumes ([rinse_volume_L]) and rinse water temperature ([rinse_temperature])
• Swab area per location ([swab_area_cm2])
• Sample volumes for rinse samples ([sample_volume_mL])

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

The analytical methods employed for vibro sifter cleaning validation must be validated to demonstrate adequate recovery, sensitivity, and accuracy to detect residues at the required levels. Recovery studies should be performed by spiking representative surfaces or swabs of the vibro sifter components with known amounts of active pharmaceutical ingredient (API) and cleaning agents.

• Recovery: Expected recovery must fall within 80-120% of the spiked concentration. This range provides confidence that the swabbing and analytical procedures effectively extract and quantify residues without significant loss or interference.
• Limit of Detection (LOD): LOD should be established using the signal-to-noise ratio method or blank sample standard deviations. The target LOD should be at least one-third of the acceptance criteria level to ensure sensitive detection of residues.
• Limit of Quantification (LOQ): LOQ should be set at a level where accuracy and precision are acceptable, typically above the LOD, often at approximately 10 times the standard deviation of the blank or lowest calibration standard. LOQ must be lower or equal to the Maximum Allowable Carryover (MACO) level.

All recovery, LOD, and LOQ data must be documented and reviewed for each cleaning validation method and equipment setup.

Acceptance Criteria Methodology: PDE/ADE-Based MACO

The primary approach for acceptance limits in the vibro sifter cleaning validation is based on the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) concepts, using a Maximum Allowable Carryover (MACO) calculation. This methodology offers a risk-based, dosage-specific, and scientifically justified framework to prevent cross-contamination between products.

MACO Calculation

The MACO limit for the vibro sifter cleaning validation is calculated as:

MACO (mg) = 
    (PDE or ADE for specific API) × (Batch size of next product) 
    ------------------------------------------------------------
    Batch size of previous product

Site-specific inputs required:

• PDE or ADE value for the API (from toxicity dossiers or ICH guidelines)
• Batch size of previous product processed in sifter (in kg or relevant units)
• Batch size of subsequent product (in kg or relevant units)

The MACO limit represents the maximum amount of residual API allowed in the vibro sifter before the next batch commences, providing a dose-based, health-protective boundary.

Surface Residue Limits

The MACO value is converted into a surface residue limit using the swabbed area:

Surface Residue Limit (µg/cm2) = (MACO × 1,000,000 µg/mg) / (Swabbed area in cm2)

Site-specific inputs required:

• Surface swabbed area of vibro sifter components ([swab_area_cm2])

This ensures the measured residue from swabbing corresponds appropriately to the MACO for effective cross-contamination control.

Legacy Acceptance Criteria (For Reference Only)

If PDE/ADE values are unavailable, legacy acceptance criteria may be applied with the understanding that these are less rigorous and should only serve as interim guidance:

• API surface residue should not exceed 10 ppm or 1/1000^th of the dose of the next product.
• These limits should be replaced by PDE/ADE based limits as soon as toxicity or safety information is available.

Detergent Residue Acceptance and Rationale

Detergent residues represent a potential source of contamination and must be controlled to safe levels to assure product safety and quality. The acceptance criteria for detergent residues are protocol and method-dependent.

Analytical Method: Typically, detergent residues are monitored via Total Organic Carbon (TOC), conductivity measurement, or specific dye assays depending on the cleaning agent properties.

• TOC Measurement: Provides a sensitive, universal indicator of organic residues and is recommended when detergents are organic compounds with complex formulations. TOC acceptance limits are based on the maximum allowable detergent residue linked to cleaning agent safety data.
• Conductivity: Useful for ionic detergents. Acceptance limits should be set at or below the conductivity of the final rinse water or validated threshold correlating with acceptable residue.
• Specific Assay: When feasible, a detergent-specific analytical method (e.g., colorimetric assay for nonionic detergents) is preferred for precise quantification and justification.

Site-specific inputs required:

• Choice of detergent analytical method ([TOC/conductivity/specific assay])
• Detergent-specific acceptance limit (expressed as mg/cm² or ppm)
• Validated method parameters: LOD, LOQ, recovery

Detergent acceptance criteria are established based on toxicological data, material safety data sheet (MSDS) limits, and regulatory guidelines to ensure no adverse impact from residual cleaning agents.

Deviations and Corrective and Preventive Actions (CAPA)

Any deviations from the cleaning validation protocol or out-of-specification results must be documented, investigated, and resolved with effective CAPA plans in place.

• Deviation Reporting: Any failure to meet acceptance limits — whether for API residues, detergent residues, or microbiological criteria (if applicable) — requires immediate deviation reporting through the Quality Management System (QMS).
• Root Cause Analysis: The investigation should determine whether issues stem from cleaning procedure inadequacies, sampling technique, analytical method failure, or equipment issues.
• Corrective Actions: Included actions may be additional cleaning cycles, procedure revision, retraining of personnel, or method revalidation.
• Preventive Actions: Updates to SOPs, incorporation of enhanced process controls, or equipment maintenance plans to prevent recurrence.

All CAPAs must be monitored for effectiveness and documented accordingly.

Plan for Continued Verification

Continued verification ensures that cleaning processes remain effective during routine production use. This plan should include:

• Frequency of Sampling: Routine cleaning verification sampling shall be performed at defined intervals, typically quarterly or after processing a limited number of batches or product changeovers.
• Sampling Scope: Critical surfaces of the vibro sifter must be swabbed and tested for residue and detergent parameters.
• Trend Analysis: Cleaning data shall be collected and trended over time to detect gradual deterioration of cleaning effectiveness.
• Requalification Triggering: Any trend towards out-of-specification results or significant process changes (including formulation or batch size) demands prompt requalification of cleaning.

Continued verification is a cornerstone of cleaning validation maintenance and GMP compliance.

Revalidation Triggers

Cleaning validation for the vibro sifter shall be revalidated under the following conditions:

• Product Change: Whenever a product with a different PDE/ADE, cleaning challenge, or batch size is introduced that may impact cleaning ability or carryover risks.
• Cleaning Procedure Changes: Changes in detergent, cleaning technique, cycle times, water quality, or equipment disassembly methods.
• Equipment Modification: Mechanical or design changes impacting surfaces in contact with product or cleaning solutions.
• Analytical Method Revision: Adoption of new methods or significant changes to existing residue detection methods.
• Out-of-Specification or Trend Deviations: Consecutive deviations in routine monitoring or significant single failures.
• Regulatory or GMP Updates: New requirements necessitating reassessment of cleaning validation scope or limits.

Annexures and Templates List

To support this protocol and procedure, the following annexures and templates should be included or referenced:

• Annex 1: Analytical Method Validation Reports (LOD, LOQ, Recovery for API and Detergent assays)
• Annex 2: Cleaning Validation Sampling Plan (swab locations, surface areas)
• Annex 3: Cleaning Validation Test Report Template (residue results, acceptance comparisons)
• Annex 4: Cleaning Procedure (SOP) for Vibro Sifter
• Annex 5: Risk Assessment Worksheet for Cleaning Validation Scope
• Annex 6: CAPA Form and Investigation Template
• Annex 7: Continued Verification Plan Schedule and Reporting Template

These documents ensure traceability, reproducibility, and consistent compliance with regulatory expectations.

Conclusion

The vibro sifter cleaning validation protocol utilizes a robust, scientific acceptance approach grounded in PDE/ADE-based MACO calculations, ensuring product safety through quantifiable, risk-driven limits. Analytical methods are validated with clear expectations for recovery and sensitivity to detect residues at levels protective of patient health and product quality. Detergent residues are controlled based on the chemical nature of cleaning agents using validated and justified methods such as TOC or conductivity.

Deviations and CAPA processes are critical components that ensure continuous improvement and regulatory compliance, while a strong continued verification plan maintains long-term cleaning effectiveness during production. Triggers for revalidation are well defined, ensuring cleaning validation remains relevant and reliable across equipment lifecycle changes. Supporting documentation through annexures and templates fosters operational consistency and GMP adherence.

Implementation of this cleaning validation approach will provide quality assurance personnel, production teams, and validation engineers with a clear, practical framework for maintaining hygienic, residue-free manufacturing conditions with the vibro sifter in oral solid dosage form production.