Capsule Filling Machine Cleaning Validation Protocol for Dry Powder Inhalation Product Contact

Purpose and Scope

The purpose of this protocol is to establish a scientifically justified and inspection-ready cleaning validation strategy for the capsule filling machine directly involved in Dry Powder Inhalation (DPI) product contact within pharmaceutical manufacturing. This document sets forth the foundational requirements and procedural framework to ensure that cleaning of the capsule filling equipment consistently meets acceptable limits for product residue, detergent residues, and microbial contamination, where applicable. The protocol ensures that residual carryover risks to subsequent batches are minimized, validated, and documented in compliance with current Good Manufacturing Practices (cGMP) and regulatory expectations.

The scope applies to all capsule filling machines used for DPI dosage forms producing capsules containing inhalation powders that come into direct contact with product during operation. This includes all product-contact parts of the equipment in the production environment. This protocol is intended for use by Quality Assurance (QA), Quality Control (QC), Validation, Production, and Engineering departments involved in cleaning validation and routine cleaning activities.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

Cleaning operations involving pharmaceutical equipment carry inherent safety risks due to exposure to cleaning agents, detergents, residual APIs, and physical hazards such as moving parts or sharp edges. Personnel performing cleaning must be trained in safe handling procedures, including chemical safety and ergonomic considerations.

Required PPE during cleaning procedures includes, but is not limited to:

• Laboratory coat or gown resistant to chemical exposure
• Chemical-resistant gloves compatible with the cleaning agents used
• Safety goggles or face shield
• Protective footwear
• Respiratory protection if aerosols or powders present inhalation risk

All PPE must be properly maintained and replaced as necessary to ensure protection and prevent contamination of the equipment and manufacturing environment.

Equipment Overview and Product-Contact Parts

The capsule filling machine used for DPI product contact is typically composed of multiple parts and assemblies that come into direct contact with powder blends and capsules during filling. The apparatus could include, but is not limited to:

All product-contact surfaces are designed to be cleaned and sanitized as per validated cleaning procedures. Non-product contact areas shall be addressed via routine GMP cleaning protocols but are excluded from the cleaning validation scope.

Cleaning Strategy Overview

The cleaning strategy for the capsule filling machine emphasizes reproducible removal of product residues and residues from cleaning agents to ensure no cross-contamination occurs between batches. The strategy includes the following high-level principles:

• Use of a validated detergent and cleaning tools capable of effectively removing DPI powders and related excipients without damaging the equipment.
• Sequential cleaning steps combining manual cleaning with automated rinsing cycles, where applicable.
• Defined cleaning hold times to prevent residue hardening and bioburden growth.
• Sampling and testing of residue levels using scientifically justified acceptance criteria based on PDE/ADE-derived Maximum Allowable Carryover (MACO).
• Detergent residue controlled through monitoring via Total Organic Carbon (TOC) or other suitable analytical methods, with acceptance limits firmly linked to cleaning agents’ characteristics.
• Microbial limits based on risk assessment of the inhalation dosage form, with environmental controls and potential bioburden testing present as appropriate.
• Periodic review and revalidation triggered by process or equipment changes.

Cleaning Agents and Tools List

Hold Times Definitions

Records and Forms List

• Cleaning Validation Protocol Document
• Cleaning Procedure SOP for Capsule Filling Machine
• Cleaning Log Sheets (for each cleaning event)
• Sampling Plan and Records
• Analytical Test Reports for Residue and Detergent Levels
• Deviation and Investigation Reports
• Equipment Maintenance Records
• Training Records for Personnel
• PPE Usage Logs

Site-Specific Inputs Required

• [detergent_name]: Name and concentration of detergent used for cleaning.
• [rinse_volume_L]: Volume of rinse water used per cleaning cycle.
• [swab_area_cm2]: Defined surface area sampled per swab or wipe.
• [max_dirty_hold_time_hours]: Maximum dirty hold time determined by validation or risk assessment.
• [max_clean_hold_time_hours]: Maximum clean hold time defined by stability and contamination risk.
• [ADE_API_mg]: Acceptable Daily Exposure value for the specific DPI active pharmaceutical ingredient (API).
• [batch_size_kg]: Batch size or maximum amount of product processed on the equipment per batch.
• [TOC_limit_ppm]: Acceptance limit for detergent residue (TOC) based on method and justification.
• Analytical method details for residue and detergent assays (to be included in subsequent protocol parts).

Capsule Filling Machine Cleaning Procedure

1. Pre-Cleaning Preparation
   1. Ensure the capsule filling machine is switched off and disconnected from the power source.
   2. Remove all remaining product residues from the machine using a clean, dry lint-free cloth or vacuum designed for pharmaceutical use.
   3. Wear appropriate personal protective equipment (PPE) including gloves, gown, and hairnet before starting the cleaning process.
   4. Assemble all cleaning tools, reagents (including [detergent_name]), rinse water, and inspection materials required for the procedure.
   5. Verify the availability of sampling materials, labels, and chain-of-custody forms.
2. Disassembly
   1. Disassemble the capsule filling machine components that are product-contact surfaces, including feed hoppers, dosator stations, tamping pins, turret parts, and any removable seals or gaskets as per the manufacturer’s instructions.
   2. Place the disassembled parts on a clean, sanitized area dedicated for cleaning.
   3. Ensure all parts have been identified, and document pieces to ensure completeness and traceability.
3. Cleaning – Wash Sequence
   1. Prepare a detergent solution using [detergent_name] at the recommended concentration specified by the manufacturer.
   2. Apply the detergent solution to all disassembled parts using appropriately sized brushes or spray equipment ensuring all product-contact surfaces are wetted.
   3. Manual scrub sensitive parts to remove product residues thoroughly, paying particular attention to crevices, joints, and threads.
   4. Allow detergent contact time of [detergent_contact_time_minutes] minutes to ensure effective soil removal.
   5. For fixed parts that cannot be disassembled, utilize automated spray nozzles or clean-in-place (CIP) systems, where applicable, following equipment-specific instructions.
4. Rinse Sequence
   1. Rinse all components thoroughly with purified water to remove detergent residues. Use a volume of [rinse_volume_L] liters per rinse cycle as per site validation data.
   2. Repeat rinsing steps a minimum of [number_of_rinses] times or until the rinse water conductivity meets the acceptance criterion of [max_conductivity_us/cm].
   3. For fixed in-situ parts, perform the rinse cycles using CIP or manual spray as applicable until validation rinse endpoint criteria are met.
   4. Check rinse water visually to confirm absence of foam or residues.
5. Drying
   1. Dry all cleaned components using lint-free towels or air drying under controlled environmental conditions (temperature [drying_temp_C], humidity < [drying_humidity_%]) to prevent microbial growth or contamination.
   2. If applicable, use filtered compressed air to remove residual moisture from hard-to-dry areas.
   3. Ensure drying time is sufficient to achieve visually dry surfaces without moisture accumulation; minimum drying time is [drying_time_minutes].
6. Reassembly
   1. Reassemble cleaned and dried components carefully in a clean environment, ensuring all parts are correctly replaced and secured as per manufacturer instructions.
   2. Verify that all gaskets and seals are intact and correctly installed.
   3. Perform a function check of moving parts to confirm proper reassembly and readiness for operation.
7. Visual Inspection
   1. Conduct a thorough visual inspection of the reassembled machine focusing on product-contact surfaces for residual soils, detergent residue, or physical damage.
   2. Use adequate lighting and magnification tools if required.
   3. Document findings and report any deviations immediately for corrective action.

Cleaning Parameters and Controls

Sampling Plan for Capsule Filling Machine Cleaning Validation

The objective of the sampling plan is to ensure that the cleaning procedure effectively removes product residues, cleaning agents, and microbial contaminants from critical surfaces of the capsule filling machine in direct contact with dry powder inhalation (DPI) products. The sampling plan is designed based on risk assessment and knowledge of high-risk contamination points.

Swabbing and Sample Collection Methodology

1. Use validated sterile swabs moistened with [swab_solvant], compatible with the analytical method employed.
2. Swab the designated surface area using a standardized pattern: horizontal strokes followed by vertical strokes ensuring complete surface coverage.
3. Apply consistent pressure and time per swab (~15 seconds per area) to increase reproducibility.
4. Immediately place the swab head into a pre-labeled sterile container containing extraction solvent.
5. Seal the container and record sample metadata, including operator name, equipment ID, location, time, and environmental conditions.
6. Transport all samples according to the chain-of-custody protocol to maintain sample integrity until analysis.

Additional Sample Types and Considerations

Sample Documentation and Record Keeping

1. Maintain a detailed cleaning and sampling logbook capturing:
   • Cleaning start and end times, personnel initials.
   • Cleaning reagent batch numbers.
   • Sampling locations, number, and sample IDs.
   • Chain-of-custody signatures and timestamps from collection through laboratory receipt.
2. Document any cleaning deviations, observations of residues or damage, and corresponding corrective actions.
3. Securely archive sampling data and cleaning records in accordance with site SOP and regulatory requirements.

Site-Specific Inputs Required

• Detergent name and concentration ([detergent_name], [detergent_concentration_%])
• Detergent contact time ([detergent_contact_time_minutes])
• Rinse volume per cycle ([rinse_volume_L]) and number of rinse cycles ([number_of_rinses])
• Maximum rinse water conductivity acceptance ([max_conductivity_us/cm])
• Swabbing area per location ([swab_area_cm2])
• Drying conditions ([drying_temp_C], [drying_humidity_%], [drying_time_minutes])
• Swab solvent information ([swab_solvant])
• Rinse sample volume for analysis ([rinse_volume_for_sampling_L])

Recovery, LOD, and LOQ Expectations

Analytical method validation is critical to ensure the reliability of the cleaning validation results. For the capsule filling machine used for Dry Powder Inhalation (DPI) product contact surfaces, the following expectations are established to guarantee method sensitivity and robustness:

Recovery studies shall be performed using spiking techniques on representative surfaces of the capsule filling machine. LOD and LOQ shall be established via calibration curve analysis with signal-to-noise ratio criteria (LOD: ~3:1; LOQ: ~10:1).

Acceptance Criteria Methodology (PDE/ADE-Based MACO)

The acceptance criteria for the residue limits on the capsule filling machine surfaces will be calculated using a PDE (Permitted Daily Exposure) or ADE (Acceptable Daily Exposure)-based MACO (Maximum Allowable Carryover) methodology. This approach aligns with current regulatory expectations for cleaning validation in pharmaceutical manufacturing of DPI dosage forms.

Conceptual Framework for MACO Calculation

1. Identify the PDE or ADE for the prior product based on toxicological assessments or established regulatory guidance.
2. Determine the maximum daily dose of the subsequent (next) product manufactured on the same equipment.
3. Calculate MACO using the formula:

   MACO (mg) = PDE or ADE of previous product (mg/day) × (Worst-case batch size of next product / Daily dose of next product)

4. Normalize MACO to the surface area of the equipment exposed to cleaning validation sampling:

   Acceptance limit = MACO / Total sampled surface area (cm²)

5. Compare analytical limits (Depends on method sensitivity) to ensure method LOQ is lower than the MACO-derived acceptance limit.

Placeholders and Site-Specific Inputs Required

• PDE or ADE for prior product: [PDE_value_mg/day]
• Maximum daily dose of next product: [Next_product_dose_mg]
• Batch size for next product: [Batch_size_units]
• Total surface area sampled on capsule filling machine: [Total_surface_area_cm2]
• Analytical method LOQ: [Method_LOQ_µg/cm2]

Example Calculation Structure

MACO (mg) = 0.1 mg/day × (100,000 units ÷ 10 mg) = 1000 mg

Acceptance Limit (µg/cm²) = (1000 mg × 1,000,000 µg/mg) / 5000 cm² = 200 µg/cm²

Analytical method LOQ must be ≤ 200 µg/cm² for valid quantification.

Legacy Criteria (Fallback)

Should PDE/ADE values not be available, legacy acceptance criteria such as:

• 10 ppm residue limit relative to the next product dose or
• 1/1000th of the therapeutic dose of the subsequent product

may be applied. These are considered conservative approaches but must be clearly justified as fallback options and documented accordingly in the validation report.

Detergent Residue Criteria and Analytical Rationale

The detergent residue limits on the capsule filling machine contact surfaces are tied directly to validated cleaning agents used during cleaning operations. It is critical to control detergent carryover due to potential toxicological effects or product quality impact, especially in DPI formulations which are inhaled directly.

Analytical Methods for Detergent Residue

• Total Organic Carbon (TOC) Analysis: Used for non-specific detection of organic detergent residues. TOC limits should be aligned with the toxicological evaluation or formulated concentration limits.
• Conductivity Measurement: Useful for ionic detergent detection; limits are set based on the lowest level deemed safe or verified by method sensitivity.
• Specific Assay (e.g., HPLC, UV): For detergents with well-defined active compounds, specific quantification provides better evidence of residue control.

Detergent Residue Acceptance Criteria

The acceptance criteria must be justified by the:

• Validated limit of the analytical test method (LOD, LOQ)
• Proportion of the detergent residue that could pose risk to product safety or efficacy
• Established cleaning agent toxicity profiles and permitted exposure limits

Site-specific detergent residue limits: [Detergent_limit_µg/cm2]

Deviations and Corrective and Preventive Actions (CAPA)

Any deviations observed during cleaning validation must be thoroughly documented, assessed, and addressed through CAPA procedures consistent with cGMP and Risk Management principles:

1. Identification and Documentation: Document deviation details from cleaning validation protocols, including analytical results, procedural lapses, or equipment malfunction.
2. Impact Assessment: Assess impact on product safety, quality, and compliance.
3. Root Cause Analysis: Investigate underlying causes—potentially including inadequate cleaning procedure, analytical method gaps, operator error, or equipment issues.
4. CAPA Implementation: Define and implement corrective measures (e.g., re-training, equipment repair, cleaning procedure adjustments) and preventive measures to avoid recurrence.
5. Revalidation: Conduct targeted revalidation or additional sampling rounds, depending on deviation severity.
6. Regulatory Reporting: Ensure deviations and CAPA are reported according to internal policies and regulatory requirements.

Continued Verification Plan

Cleaning validation is not a one-time event and requires a robust continued verification plan to ensure ongoing control over capsule filling machine cleanliness.

Records from continued verification shall be reviewed periodically by QA and Validation teams to identify trends warranting investigation or action.

Revalidation Triggers

Revalidation of the capsule filling machine cleaning procedure and acceptance criteria will be initiated upon the occurrence of any of the following triggers:

• Change in product formulation: Addition or removal of components impacting residue properties or cleaning difficulty.
• Change in cleaning procedure: Modifications to detergent, cleaning time, temperature, or mechanical steps.
• Change in equipment components or configuration: Including wear-related surface changes affecting residue adherence.
• Significant deviation reports: Failures or repeated excursions from acceptance criteria detected during routine verification.
• Changes in analytical methods: New test methods or sensitivity adjustments that could impact acceptance criteria interpretation.
• Regulatory updates or audit findings: New expectations requiring protocol adjustment and reassessment.

Annexures and Templates List

To facilitate standardized implementation and documentation of the capsule filling machine cleaning validation program, the following annexures and templates are included as part of this protocol package:

Conclusion

This cleaning validation protocol showcases a scientifically sound and regulatory-compliant framework for controlling residues on capsule filling machines used in DPI product manufacturing. By employing PDE/ADE-based MACO acceptance criteria, methodically validated analytical approaches, and a risk-driven detergent residue rationale, the program ensures patient safety and product quality. The outlined deviation management and continuous verification plans provide ongoing assurance of effective cleaning performance. Revalidation triggers are clearly defined to maintain long-term compliance and responsiveness to process changes. Together with comprehensive annexures and templates, this document facilitates a robust, inspection-ready cleaning validation system that meets contemporary pharmaceutical manufacturing expectations.