Validated Cleaning Protocol for Centrifugal Sifter in Oral Solid Dosage Production

Purpose and Scope

The purpose of this Cleaning Validation Protocol is to establish and document standardized procedures for cleaning the centrifugal sifter used in the manufacture of oral solid dosage (OSD) forms. The objective is to ensure that the equipment is consistently cleaned to a defined acceptance criteria, preventing cross-contamination and guaranteeing product quality and patient safety.

This protocol applies specifically to the centrifugal sifter equipment utilized in the processing lines for oral solid dosage products. It defines the responsibilities, required safety measures, and cleaning strategy overview, along with the list of cleaning agents and tools used. This document also instructs on the definitions of hold times and the necessary records and forms associated with cleaning validation activities.

All cleaning validation activities must comply with current Good Manufacturing Practice (cGMP), applicable regulatory requirements (FDA, EMA, ICH Q7/Q9), and internal company quality policies.

Definitions and Abbreviations

• Centrifugal Sifter: A mechanical device used to separate and classify powders by particle size through centrifugal force in OSD manufacturing.
• Cleaning Validation (CV): Documented evidence that cleaning procedures consistently remove residues to predetermined safe limits.
• Maximum Allowable Carryover (MACO): The maximum amount of residue of the previous product or cleaning agent allowed in the subsequent product batch without risk to patient safety or product quality.
• Permitted Daily Exposure (PDE): A toxicological safe limit for the daily intake of a contaminant, utilized to calculate MACO.
• Analytical Method: A validated test method such as HPLC, TOC, conductivity, or swab analysis that confirms cleaning success.
• Hold Time: The maximum time allowed between equipment use and cleaning start (Dirty Hold Time) or between cleaning completion and next use (Clean Hold Time).
• TOC: Total Organic Carbon analysis for residue detection of organic compounds including detergents and product residues.
• PPE: Personal Protective Equipment.
• SOP: Standard Operating Procedure.
• OSD: Oral Solid Dosage forms.

Responsibilities

• Quality Assurance (QA): Review and approve the cleaning validation protocol, supervise validation activities, verify acceptance criteria adherence, and authorize documentation release.
• Quality Control (QC): Perform analytical testing of cleaning samples (swabs, rinses), report results, and ensure methods are fit-for-purpose and validated.
• Validation Team: Develop and execute cleaning validation protocols, monitor compliance, document results, and manage protocol deviations.
• Production Operators: Perform routine equipment cleaning as per established procedures, gather cleaning samples under supervision, and maintain cleaning logs.
• Engineering / Maintenance: Support equipment disassembly and reassembly required for cleaning, ensure equipment design permits effective cleaning, and report any defects impacting cleanability.
• Hygiene/Sanitation Personnel: Assist in cleaning tools preparation, ensure cleaning stations are equipped, and verify cleaning agents meet required specifications.

Safety and Personal Protective Equipment (PPE)

Cleaning personnel must strictly comply with site safety protocols and wear appropriate PPE to prevent exposure to hazardous residues, cleaning chemicals, and mechanical injury. Recommended PPE includes:

• Chemical-resistant gloves compatible with [detergent_name]
• Protective goggles or face shield
• Long sleeve lab coat or coverall
• Dust mask or particulate respirator when dry residues or powders are disturbed
• Safety shoes

Personnel must receive training on safe handling of detergents, equipment hazards, and emergency response procedures. Material Safety Data Sheets (MSDS) for all cleaning agents shall be accessible in the cleaning area.

Equipment Overview and Product-Contact Parts

The centrifugal sifter is a key processing unit used to screen and classify powders in oral solid dosage manufacturing. Its primary function relies on centrifugal force to separate fine powders ensuring uniform particle size distribution in the final blend.

Main product-contact parts include:

• Sifting screen (mesh or perforated plate)
• Feed inlet and outlet chutes
• Internal sieve chamber and housing walls
• Drive shaft and rotors in contact with product
• Any clamps, seals, or gaskets in contact with powders

Non product-contact parts: Motor assembly, external housing not in contact with powders, control panels.

Material of construction: Stainless steel 316L or site-specific grade, ensuring chemical compatibility with cleaning agents and stability under cleaning conditions.

All product-contact surfaces must be smooth, without crevices or rough welds that can harbor product residues, facilitating effective cleaning.

Cleaning Strategy Overview

The cleaning strategy for the centrifugal sifter combines mechanical and chemical steps designed to effectively remove product residues, potential cross-contamination, and cleaning agent residues. The approach consists of:

• Pre-cleaning: Removal of gross product residues by manual brushing, vacuuming, or compressed air blow-off where applicable.
• Detergent Wash: Applying [detergent_name] solution at specified concentration and temperature to emulsify and loosen residual powders and oils.
• Rinse Step: Thorough rinsing using potable water to remove detergent and dissolved residues; volume and pressure specified as [rinse_volume_L] and [rinse_pressure_bar].
• Final Rinse and Drying: Multiple rinses with purified water or equivalent, followed by air drying or forced drying to remove residual moisture.
• Sampling for Validation: Swab and rinse samples collected post-cleaning for analytical verification.

This multipoint cleaning process is designed accounting for the complexity of the centrifugal sifter geometry and product variety within the OSD category. Validation data will ensure reproducibility and robustness of this cleaning strategy.

Cleaning Agents and Tools List

• Cleaning Agents:
  • [detergent_name] – Non-ionic/neutral detergent confirmed compatible with equipment materials and product residues
  • Potable water for pre-rinse steps
  • Purified Water for final rinse steps
• Cleaning Tools:
  • Soft nylon brushes with FDA-approved bristles for manual scrubbing
  • Lint-free swabs for surface sampling with defined swab area [swab_area_cm2]
  • Buckets, spray guns, or automated spray devices capable of delivering detergent and rinse water at controlled temperature and pressure
  • Cleaning cloths free from lint or contaminants
  • Personal protective equipment (outlined in Safety section)

Definitions of Hold Times

To maintain product quality and ensure cleaning effectiveness, defined hold times are critical. These are specified as:

• Dirty Hold Time: The maximum allowable interval between the end of production and the start of cleaning. Prolonged delay may result in dried residues, increasing cleaning difficulty and risk. Recommended to limit to [dirty_hold_time_hours] hours.
• Clean Hold Time: The maximum allowable interval between completion of cleaning and equipment re-use or sterile closure. Excessive hold time can increase risk of microbial proliferation or contamination buildup, recommended limit is [clean_hold_time_hours] hours.

Required Records and Forms

Complete and accurate documentation supports compliance and traceability throughout the cleaning validation lifecycle. The following records and forms are mandatory:

• Cleaning Validation Protocol Document: Approval of scope, methods, and acceptance criteria.
• Cleaning Procedure SOP: Stepwise cleaning instructions for production operators.
• Cleaning Batch Record / Log: Documentation of cleaning execution including date, times, personnel, cleaning agents, and hold times.
• Cleaning Sampling Forms: Swab and rinse sample collection data sheets specifying sample location, method, and batch number.
• Analytical Test Reports: Results from QC testing laboratories for residue analysis.
• Deviation and Investigation Records: Any incidents during cleaning or testing.
• Training Records: Evidence personnel are trained on validated cleaning procedures and safety.
• Equipment Maintenance Log: Records of equipment status impacting cleanability.

All documentation must be maintained according to site-specific document retention policies, ensuring easy retrieval for regulatory inspections and internal audits.

Centrifugal Sifter Cleaning Procedure

Pre-Cleaning Preparation

Before beginning the cleaning of the centrifugal sifter, ensure that all safety and personal protective equipment (PPE) requirements are met, including gloves, goggles, and lab coat. Confirm that the equipment is completely disconnected from all power sources and that no residues or bulk materials remain inside the unit.

• Remove all product from the sifter and collect in designated containers per SOP for material handling.
• Inspect the equipment for any visible signs of damage or wear and record findings in the cleaning log.
• Prepare all cleaning agents, tools, and materials needed: [detergent_name], cleaning brushes, lint-free cloths, swabs, and rinse water at [rinse_temperature °C].

Disassembly

Disassemble the centrifugal sifter carefully to allow for thorough cleaning of all contact surfaces.

• Remove the sieve screen assembly, rotor, blades, and any accessible seals as per the equipment manual.
• Place all disassembled parts on a clean, sanitized surface dedicated for cleaning and drying.
• Document disassembly steps and confirm all parts have been removed in the cleaning log.

Cleaning Sequence

Follow the stepwise cleaning procedure to ensure removal of product residues and cleaning agents.

Drying

• Allow all disassembled parts and internal surfaces of the main sifter housing to air dry in a clean, dust-free environment or use nitrogen or filtered air blowers.
• Ensure complete drying verified visually and, if necessary, by using residual moisture detection methods.
• Document drying time and conditions.

Reassembly

• Carefully reassemble the centrifugal sifter following the equipment manufacturer’s instructions.
• Verify that all seals, screens, and fasteners are correctly positioned and secured.
• Perform a functional check to confirm the sifter operates smoothly after assembly.
• Record reassembly completion and any deviations observed.

Visual Inspection

• Conduct a detailed visual inspection of all contact surfaces inside and outside of the centrifugal sifter for any remaining residues or contaminants.
• Use a magnifying glass or borescope if necessary to inspect hard-to-see areas.
• Ensure surfaces are free from discoloration, staining, and residual material.
• Record inspection results and certify that the sifter is visually clean and acceptable for use.

Cleaning Parameters and Control Table

Sampling Plan for Centrifugal Sifter Cleaning Validation

Sampling Locations

The sampling locations have been selected based on risk of residual retention, ease of access, and representative surfaces frequently in contact with the product or cleaning agent. All areas must be sampled using appropriately validated swabs or rinse techniques.

Sampling Procedure

• Wear fresh gloves before each sampling to avoid cross-contamination.
• Use sterile, pre-moistened swabs (with validated extraction solution) for contact surface sampling.
• Swab defined areas following a consistent pattern: horizontal strokes followed by vertical strokes covering the entire swab area.
• Place swabs immediately into labeled collection tubes containing extraction solution.
• For rinse samples, collect final rinse water from the equipment outlet into a sterile container. Ensure at least [rinse_sample_volume_mL] of rinse is collected for analysis.
• Label all samples with date, equipment ID, sampling location, and operator initials.
• Transport samples to the testing laboratory in temperature-controlled conditions as per SOP.

Sampling Frequency and Documentation

• Sampling during initial cleaning validation runs: Collect comprehensive samples as outlined.
• Routine cleaning verification sampling: Conduct a reduced set based on risk assessment, focusing on key locations.
• Document all sampling details on the Cleaning Validation Sampling Template, including:

Sampling Tools and Materials

• Sterile swabs compatible with the planned analytical methods (e.g., TOC, HPLC).
• Swab extraction solution validated to recover residues effectively.
• Sterile, labeled sample containers for rinse collection.
• Conductivity meter and pH strips for on-site monitoring as needed.
• Disposable gloves and appropriate PPE.
• Validated cleaning logs and sampling record forms.

Site-Specific Inputs Required

• [detergent_name]: Specify detergent/cleaning agent used
• [rinse_volume_L], [rinse_volume_L_final]: Volume of water used per rinse step
• [detergent_concentration % w/v]: Concentration of detergent solution applied
• [detergent_temp °C]: Temperature of detergent during cleaning step
• [contact_time_minutes]: Duration detergent is applied on surfaces
• [drying_time_hours]: Minimum drying period before reassembly
• [swab_area_cm2]: Defined area swabbed at each sampling point
• [rinse_sample_volume_mL]: Volume of final rinse sample collected for testing
• [conductivity_limit]: Maximum acceptable conductivity of final rinse water

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

For centrifugal sifter cleaning validation, establishing precise recovery, LOD, and LOQ parameters is critical to ensure accurate and reproducible residue quantification. Recovery studies will be performed using defined spiked samples on representative sampling surfaces of the centrifugal sifter, such as sieve screens and contact stainless steel surfaces.

• Recovery: Expected recovery of active pharmaceutical ingredient (API) and detergent residues should be within 90–110% of the spiked amount across all sampling media. Recovery testing involves spiking known quantities of API and detergent onto sampling coupons, swabs, or rinse samples, followed by analysis by validated analytical methods.
• LOD: The LOD for each analyte (API, detergent residues, cleaning agents) must be sufficiently sensitive to detect residues at levels at least ten times lower than the established acceptance criteria, typically in the low microgram or nanogram range per sample.
• LOQ: The LOQ should represent the lowest quantifiable concentration of residue with acceptable accuracy and precision, generally no higher than the allowable carryover limit defined by PDE/ADE calculations. For example, LOQ must enable precise quantification at or below 0.1 ppm residue levels depending on the dosage and residue risk.

Recovery, LOD, and LOQ validation will be documented and periodically re-evaluated during the continued verification phase.

Acceptance Criteria Methodology

The acceptance criteria for the centrifugal sifter cleaning validation are established primarily via the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) based Maximum Allowable Carryover (MACO) methodology. This approach ensures patient safety by limiting cross-contamination to levels below those considered to have any toxicological or pharmacological risk.

PDE/ADE-Based MACO Approach

The PDE/ADE MACO methodology relies on scientifically established exposure limits for the API(s) involved in the manufacturing process and applies them to calculate cleaning acceptance limits on equipment surfaces. The following equation describes the calculation of MACO:

MACO (mg) = (PDE or ADE, mg/day) × (Batch Size of Next Product, kg) / (Maximum Daily Dose of Previous Product, mg)

The MACO is then converted into surface residue limits corresponding to the equipment surface area to be cleaned and sampled.

Key Parameters and Placeholders

• PDE/ADE values for each API: [API_PDE_mg_day]
• Batch size of next product (oral solid dosage form): [Batch_Size_kg]
• Maximum daily dose of previous product: [Max_Daily_Dose_mg]
• Surface area of centrifugal sifter in contact with product: [Surface_Area_cm2]
• Swab/sample area: [Swab_Area_cm2]

Example Acceptance Limit Calculation

Assuming the PDE is 0.1 mg/day, batch size of next product is 100 kg, and maximum daily dose of prior product is 500 mg, surface area of equipment 2000 cm², the cleaning limit per cm² is derived as:

MACO = (0.1 mg/day) × (100 kg) / (500 mg) = 0.02 mg
Acceptance limit/cm2 = 0.02 mg / 2000 cm2 = 10 ng/cm2

Analytical methods and sampling will target detection and quantification of residue below this limit with appropriate safety margins.

Legacy Acceptance Criteria (Fallback)

In instances where PDE/ADE data is unavailable, legacy cleaning acceptance criteria may be used cautiously as a fallback:

• Not exceeding 10 ppm residue on equipment surface by weight (wt/wt) or ADI-based limit.
• Or, residue ≤ 1/1000 of the minimum therapeutic dose delivered by the equipment.

These legacy criteria are recognized but considered inferior to the PDE/ADE MACO method. Such fallback usage requires justification and approval by QA and validation teams.

Detergent Residue Rationale and Analytical Method Selection

Detergent residues can impact product quality by causing contamination, interaction with APIs, or affecting product stability. Therefore, detergent residues must be monitored post-cleaning with defined acceptance criteria tied to validated methodologies.

Analytical Approach for Detergent Residues

The following analytical methods may be used for detection of residual detergent on the centrifugal sifter surfaces:

• Total Organic Carbon (TOC): Detects any leftover organic material (including detergent residues) by measuring carbon content. Useful for general screening and verifying rinse effectiveness.
• Conductivity Measurement: For ionic detergents, conductivity assessment provides rapid indication of residual ionic detergent content.
• Specific Assay (UV/Colorimetric/HPLC): Where specific detergent chemistry is known, tailored assays enable precise quantification of residual cleaning agents.

TOC is typically employed as a broad screening tool with justified acceptance criteria expressed in parts per million (ppm) or mg/L supported by rinse volume and surface area.

Detergent Acceptance Criteria

Detergent residue acceptance is linked to maximum allowable limits supported by toxicological evaluation, cleaning agent residual carryover risk, and validated detection methods.

• Set maximum allowable detergent residue limit as [Detergent_Limit_mg/cm2] based on safety and compatibility assessments.
• TOC or specific assay detection limit should be below this acceptance criterion.
• Conductivity or colorimetric methods should be validated to differentiate acceptable from unacceptable residue levels.

Detergent residue limits must be defined site-specifically in validation documents with relevant controls during cleaning runs.

Deviations and Corrective and Preventive Actions (CAPA)

Any deviations during cleaning validation testing or routine cleaning verification—such as residues above acceptance criteria, sample contamination, or analytical method failure—must be documented in a deviation report.

• Immediate investigation to identify root cause, e.g., inadequate cleaning procedure, equipment malfunction, or sampling errors.
• CAPA development to correct identified issues: revise cleaning parameters, enhance operator training, requalify cleaning agents, or service equipment.
• Revalidation or supplemental cleaning validation study triggered by critical deviations impacting product safety.
• Trend analysis of deviations to prevent recurrence.

All deviation and CAPA activities must be formally reviewed and approved by QA and validation teams.

Continued Verification Plan

Cleaning validation of the centrifugal sifter is not a one-time activity; an ongoing continued verification program ensures sustained cleaning efficacy over the equipment lifecycle. This program includes:

• Routine environmental and product residue monitoring on critical equipment surfaces at defined intervals.
• Post-maintenance and post-repair cleaning verification.
• Sampling frequency may be monthly or batch-based depending on production risk assessment.
• Continuous monitoring of detergent residues, rinse efficacy, and microbial results if risk-assessed as applicable.
• Periodic method revalidation as necessary, aligned with analytical method performance and regulatory expectations.

Results of continued verification are reviewed and trended to detect any drift in cleaning performance, with necessary investigations and CAPAs as indicated.

Revalidation Triggers

Revalidation of centrifugal sifter cleaning procedures should be executed when any of the following occur:

• Changes in product formulation or significant API potency alterations affecting residue carryover risk.
• Change in batch size or maximum daily dose impacting acceptance limits.
• Modification or replacement of cleaning agents or detergents.
• Changes in cleaning equipment design or critical equipment components.
• Failures identified during routine continued verification sampling or cleaning validation deviations.
• Significant process changes in manufacturing process affecting equipment usage or exposure.
• Regulatory agency requests or audit findings requiring updated validation.

Each trigger prompts a full or partial revalidation with documentation of rationale, testing, and approval.

Annexures and Templates

The following annexures and templates shall be included in the cleaning validation documentation package for the centrifugal sifter:

• Annexure A: Cleaning Validation Master Plan Excerpt – PDE/ADE Methodology Description
• Annexure B: Analytical Method Validation Reports (Recovery, LOD, LOQ Data)
• Annexure C: Cleaning Procedure SOP – Stepwise Cleaning Instructions for Centrifugal Sifter
• Annexure D: Swab and Rinse Sampling Plan and Maps
• Annexure E: Cleaning Validation Batch Execution Records and Sampling Logs
• Annexure F: Acceptance Criteria Calculation Worksheets for API and Detergent Residues
• Annexure G: Deviation and CAPA Templates related to Cleaning Validation
• Annexure H: Continued Verification Schedule and Trend Analysis Reports
• Annexure I: Revalidation Rationale and Change Control Forms

Conclusion

The centrifugal sifter cleaning validation protocol governed by PDE/ADE-based MACO methodology ensures robust control over cross-contamination risks inherent in oral solid dosage manufacturing. By precisely defining recovery, LOD, and LOQ expectations, and tying detergent residue limits to validated analytical methods, the protocol assures both patient safety and product quality integrity.

Strict governance through deviation management, continual cleaning verification, and clearly defined revalidation triggers embeds quality at every stage of equipment lifecycle and manufacturing cycle. Inclusion of comprehensive annexures supports methodical execution and regulatory readiness.

Ultimately, the validated cleaning protocol for the centrifugal sifter aligns with cGMP principles, meeting internal standards and regulatory expectations for cleaning validation in pharmaceutical solid dosage manufacturing environments.