Cleaning Validation Protocol and Procedures for Co-Mill and Cone Mill Equipment in Oral Solid Dosage Manufacturing

Purpose and Scope

This document establishes a comprehensive cleaning validation protocol and standard operating procedure for co-mill and cone mill equipment utilized in the manufacturing of oral solid dosage forms. The intent is to ensure that cleaning processes consistently reduce product residues, cleaning agents, and potential contaminants to levels that meet predefined acceptance criteria based on toxicological and regulatory considerations.

The protocol defines the responsibilities, cleaning strategy, equipment and contact surfaces, safety parameters, and record-keeping requirements necessary to assure validated cleaning performance and regulatory compliance. This protocol applies to all co-mill and cone mill equipment used to process oral solid dosage forms within the manufacturing facility.

This document supports cross-functional teams encompassing Quality Assurance (QA), Quality Control (QC), Validation, Production, and Engineering departments involved in cleaning validation activities.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

Personnel performing cleaning and sampling activities must adhere to established safety protocols to minimize exposure to residual APIs, excipients, cleaning agents, and dust from milling operations. The following PPE is recommended:

• Protective lab coat or disposable coveralls resistant to chemical exposure
• Safety goggles or face shield to protect eyes from splashes
• Chemical-resistant gloves (specify material based on cleaning agents used)
• Dust/mist respirator with appropriate filtration rating
• Hair nets and beard covers to avoid contamination
• Closed-toe, non-slip safety shoes

All personnel must be trained on chemical hazards, spill response, and emergency procedures prior to performing cleaning validation tasks.

Equipment Overview and Product-Contact Parts Description

The primary equipment subject to cleaning validation are the co-mill and cone mill systems used for size reduction of oral solid dosage formulations. These mills consist of the following product-contact parts:

• Feed hopper: Stainless steel container where material is loaded
• Feeding chute: The conduit directing material into the milling chamber
• Milling chamber (conical section): The main milling zone containing the conical sieve and rotor
• Sieve screen: Stainless steel mesh that controls particle size
• Rotor assembly: Rotating blade system responsible for milling action
• Discharge outlet: The exit point for milled material
• Collection bin or hopper: Container collecting milled product, if applicable

All product-contact surfaces are fabricated from stainless steel 316L or equivalent sanitary-grade materials. Surface finishes comply with cGMP standards to facilitate cleaning.

Equipment may have additional auxiliary contact components such as seals, gaskets (validated to prevent residues accumulation), and inspection windows. These parts shall be included in the cleaning validation scope.

Cleaning Strategy Overview (High-Level)

The cleaning approach incorporates a risk-based methodology focusing on residue removal for active pharmaceutical ingredients (APIs), excipients, and cleaning agents to prevent cross-contamination and ensure patient safety. Key elements include:

• Initial dry cleaning: Manual removal of gross product residue using brushes, scrapers, and vacuuming
• Wet cleaning: Application of defined detergent solutions ([detergent_name]) with controlled contact time and temperature
• Rinsing: Multiple rinses with purified water, each totaling approximately [rinse_volume_L] liters
• Cleaning aids and tools: Dedicated brushes, swabs, cleanroom wipes compatible with APIs and detergents
• Verification samples: Systematic swabbing of critical surfaces and collection of rinse samples per validated sampling plan
• Drying: Post-cleaning drying in controlled environment to prevent microbial growth if applicable

The cleaning process will be periodically revalidated based on equipment use frequency, product changes, or process modifications.

Cleaning Agents and Tools List

Hold Times Definitions

Hold times are determined based on formulation characteristics, microbial risk assessment, and equipment materials, and should be documented for each cleaning cycle.

Records and Forms

• Cleaning Validation Protocol and Report Forms
• Cleaning Procedure Execution Logs
• Sampling Sheets (Swab and Rinse Labeling)
• Analytical Testing Reports (Residue Analysis, TOC, Conductivity, Specific Assay Results)
• Personal Protective Equipment Use Logs
• Equipment Inspection and Maintenance Records
• Non-conformance and Deviation Records
• Training Records for Personnel performing Cleaning and Validation

Site-specific Inputs Required

• Detergent name and formulation details ([detergent_name])
• Typical rinse volume for wet cleaning ([rinse_volume_L])
• Swab sampling surface area to define residue limits ([swab_area_cm2])
• Hold time limits for dirty and clean states ([dirty_hold_time_hours], [clean_hold_time_hours])
• Specific equipment design or component variations impacting cleaning
• Cleaning solution preparation parameters: temperature, concentration, contact time
• Defined cleaning frequency and revalidation intervals
• Acceptance criteria numerical values based on site toxicological risk assessments (to be included in Part B)
• Analytical laboratory capabilities and validated methods for residue detection

Co-Mill / Cone Mill Cleaning Procedure

1. Pre-cleaning Preparation
   1. Ensure all personnel performing cleaning are trained and wearing appropriate PPE.
   2. Confirm the mill is stopped and isolated from power sources.
   3. Remove any bulk product residue from the mill using a clean, dry brush or vacuum designed for pharmaceutical use.
   4. Inspect the mill exterior and immediate surrounding area for visible residue or dust and remove as needed.
2. Disassembly of Co-Mill / Cone Mill Components
   1. Carefully disassemble the cone mill elements including feed hopper, milling chamber, screens, and base parts according to manufacturer’s guidelines.
   2. Place disassembled parts on sanitized cleaning trays to avoid cross-contamination.
   3. Visually inspect all parts for visible product residues and damage.
3. Cleaning of Mill Components – Wash Phase
   1. Prepare wash solutions using specified [detergent_name] at the recommended concentration as per site SOP.
   2. Immerse parts fully in the prepared detergent solution. If immersion is not possible, use clean soft brushes or sponge soaked in detergent solution.
   3. Scrub all contact surfaces thoroughly to remove visible residues.
   4. Recirculate detergent solution through fixed mill surfaces where possible (e.g., spray or CIP if applicable).
   5. Allow detergent action for a minimum contact time of [detergent_contact_time_minutes] minutes.
4. Rinse Sequence
   1. Rinse all washed parts and fixed surfaces with purified water to remove detergent residues thoroughly.
   2. Rinse volume: minimum [rinse_volume_L] liters per rinse cycle with a minimum of two rinse cycles.
   3. Where applicable, perform final rinse using WFI (Water for Injection) or USP grade water to ensure removal of microbial and endotoxin risks.
   4. Inspect rinse water clarity; if turbidity or residue is noted, repeat rinse sequence.
5. Drying of Components
   1. Use clean, lint-free cloths or controlled air dryers (filtered and validated compressed air) to dry all parts completely.
   2. Place parts in a sanitized drying cabinet at [drying_temperature_C] °C for [drying_time_minutes] as per site procedure or dry naturally in a controlled environment.
   3. Ensure no moisture is retained as it can promote microbial growth or affect the next product.
6. Reassembly of Mill
   1. Reassemble all components of the cone mill carefully to original configuration.
   2. Ensure all fasteners are tightened to manufacturer’s torque specifications.
   3. Check for smooth rotational movement and proper alignment.
7. Visual Inspection
   1. Inspect all exposed and internal surfaces for any residual dust, stains, or visible contaminants using an approved flashlight and magnification tools where necessary.
   2. Document inspection results using standard checklists.
   3. If residues are detected, repeat appropriate cleaning steps before sampling.

Cleaning Process Parameter Table

Sampling Plan for Cleaning Validation

Sampling Procedure and Handling

1. Collect all samples immediately after cleaning and visual inspection to ensure sampling represents post-clean condition.
2. Use sterile swabs moistened with a validated solvent ([swab_solvent]) specific to active residues and detergent components.
3. Document each sample with unique laboratory sample ID including date, time, equipment ID, location, and collector’s signature.
4. Maintain chain-of-custody by recording transfer of samples from collection to laboratory for analysis.
5. Transport samples in cooled containers at 2–8 °C when delays beyond 2 hours before analysis are expected.
6. Perform analyses for active pharmaceutical ingredient (API) residues using validated analytical methods aligned to the product specifics, and detergent residues using TOC or specially validated assay.
7. Store records and analytical results as per site data integrity and documentation policies.

Site-Specific Inputs Required

• [detergent_name]: Detergent/cleaning agent identified by site formulation and validated for material compatibility
• [detergent_concentration]: Detergent concentration to achieve effective residue removal
• [detergent_contact_time_minutes]: Contact time validated for bioburden and residue removal
• [rinse_volume_L]: Volume of purified water per rinse cycle sufficient to remove detergent residues
• [drying_temperature_C] & [drying_time_minutes]: Drying environmental parameters
• [swab_area_cm2]: Swab sampling surface area to standardize residue collection
• [swab_solvent]: Validated extraction solvent for swabbing API and detergent residues

Cleaning Verification and Sampling Plan

Visual Inspection

1. Conduct a thorough visual inspection of all disassembled parts and fixed mill surfaces to confirm absence of visible residues or contaminants.
2. Use adequate lighting and magnification aids where necessary to improve residue detection sensitivity.
3. Document findings, capturing photographic evidence when available for traceability.

Sampling Strategy

1. Identify critical cleaning sites on both fixed and disassembled components based on risk assessment and previous contamination study.
2. Utilize swabbing and rinsing techniques as appropriate for surface residue collection.
3. Swab sampling to cover an area of [swab_area_cm2] cm² per site using validated swab materials compatible with analytical methods.
4. For rinse sampling, collect defined volumes ([rinse_sample_volume_mL]) of final rinse water from fixed equipment after completion of the rinse sequence.
5. Label and handle samples under controlled conditions to prevent cross-contamination and degradation prior to analysis.

Analytical Methods for Residue Detection

1. Product Residue Assay: Apply validated HPLC/UV/Other specific assays targeting active pharmaceutical ingredient (API) residues to quantify potential carryover.
2. Detergent Residue Assessment: Utilize Total Organic Carbon (TOC) or conductivity measurement calibrated for [detergent_name] to determine residual detergent levels.
3. Microbial Limits (If applicable): Employ bioburden testing protocols per USP microbial limit tests if risk assessment indicates potential microbial contamination.

Acceptance Criteria

Carryover Limits Based on PDE/ADE and MACO

Acceptance limits for product residues shall be calculated using the PDE (Permitted Daily Exposure) or ADE (Acceptable Daily Exposure) and Maximum Allowable Carryover (MACO) concept:

1. Determine the lowest PDE/ADE value for the product components as per regulatory toxicological data.
2. Calculate MACO by adjusting PDE/ADE for worst-case patient weight and maximum daily dosage of the next product manufactured.
3. MACO calculation formula example:
   
   MACO = (PDE or ADE × Patient Weight) / Maximum Daily Dose of Next Product
4. Cleaning acceptance limits equal or below MACO value expressed as residual API mass per cleaned surface area or batch.

Note: Placeholders such as [PDE_value], [patient_weight_kg], [max_daily_dose_mg], and [calculated_MACO] must be site-specifically input.

Detergent Residue Limits

1. Residual detergent levels must not exceed the limit established by the analytical method used, e.g., TOC limit of [TOC_limit_ppm] ppm or conductivity of [conductivity_limit_µS/cm].
2. Limits shall reflect safety and product quality considerations specific to detergent toxicity and product sensitivity.

Microbial Load Limits (Risk-Based)

If risk assessment mandates microbial control:

1. Limit bioburden to less than [microbial_limit_cfu/cm2] colony-forming units (CFU) per cm² for swab samples.
2. Conform to USP microbial limit tests or site-specific microbiological acceptance criteria.

Legacy Limits as Fallback (If Required)

• In absence of PDE/ADE data, apply legacy approach:
  • Product residue acceptance criteria ≤ 10 ppm or ≤1/1000 of the minimum therapeutic dose.

Documentation and Reporting

1. Record all cleaning activities, sampling details, and analytical results in controlled cleaning validation batch records.
2. Document any deviations or anomalies found during cleaning, sampling, or analysis processes.
3. Compile a comprehensive validation report including methodology, acceptance criteria calculations, and conclusions on cleaning effectiveness.
4. Retain records in compliance with data integrity and regulatory requirements for audit and inspection readiness.

Site-Specific Inputs Required

• [detergent_name]
• [rinse_volume_L]
• [detergent_contact_time_minutes]
• [swab_area_cm2]
• [drying_temperature_C]
• [drying_time_minutes]
• [rinse_sample_volume_mL]
• [PDE_value]
• [patient_weight_kg]
• [max_daily_dose_mg]
• [calculated_MACO]
• [TOC_limit_ppm] or [conductivity_limit_µS/cm]
• [microbial_limit_cfu/cm2]

Recovery, LOD, and LOQ Expectations

Analytical methods employed for co mill cone mill cleaning validation must demonstrate robust sensitivity and specificity to reliably detect residual active pharmaceutical ingredients (APIs), cleaning agents, and any potential cross-contaminants. Method validation parameters including recovery, limit of detection (LOD), and limit of quantification (LOQ) shall be established and documented prior to acceptance of cleaning validation results.

Recovery Studies: Recovery rates should be evaluated for all targeted residues on representative surfaces and matrices mirroring actual production conditions. Acceptable recovery is generally ≥ 80%, but specific site protocols may dictate tighter ranges based on historical data and method performance.

Limit of Detection (LOD): LOD defines the lowest residue concentration that the analytical method can detect but not necessarily quantify precisely. This should meet or exceed the sensitivity to detect residues at or below the Maximum Allowable Carryover (MACO) thresholds detailed below.

Limit of Quantification (LOQ): LOQ is the minimum concentration at which the residue can be quantitatively measured with acceptable precision and accuracy, typically required to be below the established MACO limits to ensure legitimate pass/fail calls in cleaning validation.

All method validation reports must include documented assessments of recovery, LOD, and LOQ reflecting the specific surfaces sampled (e.g., stainless steel cones, milling chambers) and residues analyzed (e.g., API, excipients, detergents).

Acceptance Criteria Methodology

The primary approach for setting acceptance criteria in co mill cone mill cleaning validation is the use of a PDE (Permitted Daily Exposure)/ADE (Acceptable Daily Exposure)-based MACO (Maximum Allowable Carryover) methodology. This scientifically sound, risk-based strategy aligns residual acceptance limits with patient safety considerations and regulatory expectations.

PDE/ADE-Based MACO Calculation Structure

Example Calculation: Suppose the PDE for API X is 0.1 mg/day, and the maximum daily dose of the following product is 50 mg; then:

MACO = 0.1 mg/day / 50 mg = 0.002 mg API X per mg of product or per dose unit.

Cleaning residues must be limited to levels well below the MACO to ensure no cross-contamination risk to patients.

Legacy Acceptance Criteria (Fallback)

In cases where PDE/ADE values are unavailable or for low-risk products, legacy thresholds such as a maximum residue limit of 10 ppm (0.001%) or 1/1000 of the minimum therapeutic dose may be applied. This approach is considered conservative but should be phased out in favor of PDE/ADE calculations where possible.

Detergent Residue Rationale and Limits

Detergent residues are controlled due to potential toxicological and product quality risks after cleaning of the co mill cone mill. Acceptance criteria for detergent residues shall be defined based on the analytical methodology employed:

• Total Organic Carbon (TOC) Assay: Used to detect residual organic matter from detergents. Limits shall be based on the sensitivity of the finalized TOC method, typically expressed in ppm TOC per unit surface or per rinse volume.
• Conductivity Measurement: Employed for ionic detergent residue detection. Acceptance limits should relate to baseline conductivity of rinse water adjusted for detector sensitivity and expected carryover levels.
• Specific Chemical Assays: For proprietary detergents, specific quantitative methods (e.g. HPLC, UV) can be applied to establish acceptance criteria correlated to toxicological and formulation data.

The final detergent residue limit shall be scientifically justified considering:

1. The toxicological safety threshold of residual detergent components.
2. Analytical method’s limit of quantitation (LOQ) and robustness.
3. Typical rinsing efficiency and residual carryover observed during method validation.
4. Potential impact on subsequent product quality (physicochemical interactions, microbial risk).

Site-specific inputs required:

• Detergent product name and composition ([detergent_name])
• Analytical method for detergent residue quantification
• Rinse volumes and sampling surfaces ([rinse_volume_L], [swab_area_cm2])

Deviations and Corrective and Preventive Actions (CAPA)

Any deviations identified during the cleaning validation process or routine cleaning verification—such as detection of residue above acceptance limits, sampling irregularities, or analytical method failures—shall be documented and investigated thoroughly. The CAPA process should include:

1. Immediate containment actions to prevent release of out-of-specification products.
2. Root cause analysis detailing factors contributing to cleaning validation failure.
3. Review of cleaning procedure adequacy, potential modification of equipment cleaning steps, cleaning agents, or parameters.
4. Revalidation of cleaning procedure following corrective action implementation.
5. Training refreshers for production and quality personnel as appropriate.

All CAPA records must be traceable to the deviation event and include timelines, responsible personnel, and follow-up verification results.

Continued Verification Plan

Following initial cleaning validation, a systematic continued verification plan is mandatory to ensure the sustained effectiveness of cleaning procedures on the co mill cone mill. Key elements include:

1. Routine Monitoring: Periodic sampling and residue analysis per the validated sampling plan defined in Part B, scheduled typically at least annually, or more frequently for high-risk or dusty products.
2. Trend Analysis: Documentation and review of cleaning verification data for trending potential increases in residue levels, enabling early detection of process drift or equipment degradation.
3. Procedure and Equipment Review: Regular assessment of cleaning SOP adherence, equipment condition (wear, damage, surface finish), and cleaning agent effectiveness.
4. Training and Awareness: Periodic retraining of operators and QC/validation personnel on updated procedures and critical control points.

Any anomalies detected during continued verification must trigger a deviation investigation as outlined above.

Revalidation Triggers

Revalidation of the co mill cone mill cleaning process shall be conducted whenever any of the following occur:

• Major equipment modifications affecting cleaning access or surface area.
• Changes in product formulation, particularly those altering physical or chemical properties affecting cleanability.
• Introduction of new cleaning agents or modifications to detergent concentration/cleaning parameters.
• Repeated deviations in cleaning validation or continued verification exceeding acceptance criteria.
• Regulatory authority requests or findings requiring reassessment.
• Extended equipment downtime leading to potential contamination or bioburden buildup.

Revalidation shall follow the same rigorous protocols and sampling plans defined in Part B, with full documentation and robust justification.

Annexures and Templates

The following annexures and templates are to be maintained and referenced within the co mill cone mill cleaning validation documentation suite:

Conclusion

The cleaning validation of co mill cone mill equipment is a critical component in ensuring product quality and patient safety in oral solid dosage manufacturing. Employing a PDE/ADE-based MACO acceptance criterion supports scientifically justified limits tailored to product-specific risk profiles, superseding legacy thresholds. Method validation must confirm adequate recovery, detection, and quantification capabilities for all relevant residues including APIs and detergents. A comprehensive governance framework encompassing deviation management, CAPA implementation, continued verification, and structured revalidation ensures sustained compliance and process robustness over equipment lifecycle changes. Supplementary documentation and templates must be rigorously maintained to provide auditable evidence supporting all validation activities. Adhering to these principles enables pharmaceutical manufacturers to confidently demonstrate control of cross-contamination risks associated with co mill cone mill cleaning processes.