Validation Team designs the cleaning validation program including sampling plans, analytical methods, and acceptance criteria. They also ensure that protocols and reports meet internal and regulatory requirements.

Production Operators execute approved cleaning procedures correctly, identify and report deviations, and maintain cleaning logs and documentation.

Engineering maintains and calibrates cleaning equipment, supports method development for cleaning, and assists in risk evaluations related to product contact surfaces.

Safety and Personal Protective Equipment (PPE)

All personnel performing cleaning activities must adhere to established safety protocols and wear appropriate PPE to prevent exposure to cleaning agents, product residues, and physical hazards associated with the capsule filling machine.

• Safety goggles or face shield
• Chemical-resistant gloves suitable for [detergent_name]
• Protective lab coat or coverall
• Closed-toe, slip-resistant shoes
• Respiratory protection if volatile or hazardous chemicals are used

Prior to cleaning, operators should perform a hazard assessment to identify any additional PPE requirements. Emergency procedures for chemical spill and exposure must be communicated and accessible near the cleaning area.

Equipment Overview and Product-Contact Parts

The hard gelatin capsule filling machine consists of multiple components that contact the product or intermediates during capsule filling. Identifying these product-contact parts is crucial for establishing an effective cleaning validation strategy.

All product-contact parts shall be disassembled as described in the Cleaning Procedure section to ensure thorough cleaning. Ancillary equipment, such as filling hoppers and material transfer buckets in contact with product residues, are also included in the cleaning scope.

Cleaning Strategy Overview

The cleaning strategy follows a risk-based approach to ensure removal of product residues, cleaning agents, and prevention of microbial contamination. The following principles guide the strategy:

• Disassembly: Product-contact parts are disassembled from the machine frame for individual cleaning to improve detergent access and residue removal.
• Cleaning Method: Combination of manual cleaning, including scrubbing with appropriate brushes, and automated or semi-automated rinsing processes.
• Cleaning Agents: Use of validated detergent formulations ([detergent_name]) selected based on compatibility with machine materials and effective removal of product residues and microbes.
• Cleaning Cycle: Sequential cycles of detergent wash, intermediate rinsing with purified or deionized water ([rinse_volume_L]) and final rinse ensuring removal of detergent residues.
• Hold Times: Defined maximum dirty hold time post-production prevents bake-on residues; clean hold time defines re-usage interval before re-cleaning is mandated.
• Environmental Controls: Cleaning performed in controlled areas minimizing exposure to contaminants and ensuring drying of parts prior to reassembly.

Cleaning Agents and Tools List

Hold Times Definitions

Records and Forms List

The following documentation is essential to support the cleaning validation protocol and cleaning procedure:

• Cleaning Validation Protocol Document
• Cleaning Procedure (SOP) for Hard Gelatin Capsule Filling Machine
• Cleaning Batch Log Forms – recording cleaning activity details and responsible personnel
• Sampling Forms – details of surface sampling locations, swab information, and sample identifiers
• Analytical Results Reports – documentation of chemical residue and microbial testing data
• Cleaning Validation Summary Reports – evaluation of cleaning validation runs and acceptance criteria
• Equipment Maintenance and Calibration Records – documentation of cleaning tools and monitoring systems
• Deviations and Investigation Reports related to cleaning procedures

Site-Specific Inputs Required

• [detergent_name]: Specific commercial detergent product name and formulation used for cleaning
• [rinse_volume_L]: Volume of purified or water-for-injection used for intermediate and final rinses
• [swab_area_cm2]: Defined surface area used for swabbing sampling at various locations
• [dirty_hold_time_hours]: Allowed maximum time equipment can remain uncleaned post-production
• [clean_hold_time_hours]: Allowed maximum time equipment remains clean before re-cleaning is needed
• Specific cleaning tool specifications including brush types and swab brands
• Material compatibility requirements and machine assembly/disassembly instructions

Responsibilities

Safety Precautions and PPE

1. Ensure personnel wear appropriate Personal Protective Equipment (PPE) including gloves, lab coat or gown, safety goggles, and masks as necessary when performing cleaning and sampling activities.
2. Adhere to Material Safety Data Sheet (MSDS) requirements for the detergent [detergent_name] and any chemical agents used during cleaning.
3. Use appropriate tools and techniques to avoid physical injuries such as cuts or abrasions from sharp machine parts.
4. Follow lockout-tagout (LOTO) procedures to prevent accidental machine start-up during cleaning.
5. Ensure adequate ventilation in cleaning areas to mitigate exposure to chemical fumes.

Equipment Description and Critical Surfaces

Cleaning Agents and Water Quality

Site-specific Inputs Required:

• [detergent_name]
• [detergent_concentration_%]
• [rinse_volume_L]
• Water quality specifications (Purified Water / WFI)
• Microbial testing requirements including limits if applicable

Cleaning Validation Strategy and Approach

1. Risk Assessment: Perform a cross-contamination risk evaluation to determine the necessity and extent of cleaning validation for the hard gelatin capsule filling machine based on factors such as product potency, toxicity, batch size, equipment design, and previous validation data.
2. PDE/ADE and MACO Calculation: Establish cleaning acceptance limits by calculating the Maximum Allowable Carryover using the following formula:

   MACO (mg) = (PDE or ADE in mg/day) × (Smallest batch size in kg) / (Largest batch size of next product in kg)

   Where:

   • PDE (Permitted Daily Exposure) or ADE (Acceptable Daily Exposure) is sourced from toxicological data of the next product to be manufactured.
   • Batch sizes are based on manufacturing site-specific parameters.
3. Sampling Plan: Define sampling locations to target critical product-contact areas prone to residue accumulation. Sampling methods include swab sampling (surface-specific) and rinse sampling (bulk residue).
4. Analytical Methods: Use validated assay methods to quantify residual drug substances and cleaning agents, including TOC for total organic residue and specific assays for detergents or active pharmaceutical ingredients (API) if applicable.
5. Acceptance Criteria:
   • The residual API must not exceed MACO limit (mg/sample/site area).
   • Detergent residues must comply with limits established by TOC or specific assay results (site-specific limits for TOC should be justified scientifically).
   • Microbial limits should be applied on a risk basis aligned with product criticality and nature of equipment (include limits if set).
6. Legacy Acceptance Criteria: For sites using legacy criteria as fallback, the commonly applied criteria are:
   • Residual API concentration ≤10 ppm
   • Residual API concentration ≤1/1000th of the minimum therapeutic dose

Responsibilities

Clear assignment of duties and accountability is vital for the effective execution of this cleaning validation protocol. The following outlines the key roles involved:

Equipment Description and Critical Components

The hard gelatin capsule filling machine consists of multiple product-contact parts whose cleanliness is critical for preventing cross-contamination. Key components include:

Site-specific inputs required:

• Detailed equipment schematic including product-contact surfaces
• Material of construction for each part (e.g., stainless steel grade)
• List of lubricant types and compatibility with cleaning agents

Cleaning Agent and Equipment Compatibility

The selection of cleaning agents must consider efficacy against product residues and compatibility with equipment materials to prevent corrosion or damage. Recommended cleaning agents include:

• Detergents: [detergent_name] – validated for effective removal of powder and gelatin residues with minimal residue.
• Rinse Water: Purified water or WFI, volume as per validation specifics.
• Sanitizing Agents: Use only if microbial risk is identified; otherwise, thorough detergent cleaning and rinsing are sufficient.

Site-specific inputs required:

• Detergent formulation and concentration
• Detergent residue analytical method (TOC/Conductivity/Specific assay)
• Recommended rinse volumes and temperature
• Instruments/materials for cleaning (brushes, ultrasonic cleaners, etc.)

Cleaning Validation Strategy

The cleaning validation approach is designed following a risk-based framework consistent with regulatory expectations:

• Worst-Case Product Selection: Select the product with the highest toxicity, lowest PDE/ADE, or the most complex residue profile for validation.
• Sampling Methods: Combination of swab and rinse sampling targeting critical areas identified in the equipment overview.
• Analytical Methods: Use validated sensitive methods to detect residues at or below the established acceptance criteria.
• Acceptance Criteria: Based primarily on PDE/ADE-based MACO methodology. Legacy acceptance criteria (e.g., 10 ppm, 1/1000-dose) will be retained for comparison or if PDE/ADE is not available.
• Number of Cleaning Cycles: Validation includes worst-case cleaning cycles (post-production, post-maintenance).
• Hold Times: Validation of maximum allowable Hold Time – Dirty and Hold Time – Clean to ensure effective cleaning within defined timeframes.

PDE/ADE-Based MACO Methodology

The Maximum Allowable Carryover (MACO) defines the acceptable residue limit on equipment surfaces to prevent cross-contamination. MACO is calculated using the PDE or ADE according to the following structure:

Site-specific inputs required:

• PDE/ADE value for product or relevant contaminants
• Batch size of next product
• Total swab area (cm²) to be sampled

Sampling Plan

The sampling plan is designed to provide comprehensive coverage of all product-contact surfaces to demonstrate absence of unacceptable residues:

1. Identify critical cleaning locations on the hard gelatin capsule filling machine including dies, pistons, chutes, and ancillary equipment.
2. Use swab sampling for hard-to-rinse, intricate surfaces.
3. Use rinse sampling of bulk liquid collected during cleaning procedures, especially for internal aqueous pathways and large contact areas.
4. Define sample size based on surface area – typically [swab_area_cm2] per swab.
5. Include blank and positive controls for analytical validation.

Site-specific inputs required:

• Exact sampling locations mapped to equipment drawings
• Number of samples/swabs per location
• Swab and rinse sample volume and handling protocols

Analytical Method Validation and Detection Limits

The employed analytical methods must be validated specifically for:

• Specificity to detect product, detergent, and lubricant residues separately
• Limit of detection (LOD) and limit of quantification (LOQ) adequate to meet MACO-derived acceptance criteria
• Robustness and reproducibility in detecting low-level residues
• Use of TOC or specific assay for detergent residues, with rationale and calibration standards included

Site-specific inputs required:

• Analytical method protocols aligned with sampling matrices
• Calibration and validation reports for analysis

Safety Measures and Personal Protective Equipment (PPE)

To ensure personnel safety during cleaning and sampling procedures, strictly adhere to the following precautions:

Documentation and Change Control

Maintain comprehensive and contemporaneous documentation for all cleaning validation activities including:

• Approved cleaning validation protocol with version control
• Detailed batch records of cleaning procedures
• Sampling logs including locations, date/time, and personnel
• Analytical test results with raw data and interpretation
• Deviation reports and corrective action documentation

All changes to cleaning procedures or validation documents shall comply with established change control procedures and require re-approval prior to implementation.

Responsibilities

Safety and PPE Requirements

To ensure personnel safety and prevent contamination during the cleaning and sampling processes, the following personal protective equipment (PPE) must be worn at all times:

• Protective gloves resistant to cleaning chemicals
• Safety goggles or face shield to prevent splashes
• Lab coat or protective gown
• Hairnet and beard cover where applicable
• Respiratory protection if aerosolized detergents are used

All personnel must be trained in the handling of cleaning agents, awareness of chemical hazards, and emergency procedures including spill management and first aid.

Equipment and Materials

Cleaning Validation Approach

The cleaning validation strategy is based on a risk-assessed, scientifically justified PDE/ADE-based MACO approach as the primary methodology, supplemented by legacy acceptance rules where needed.

MACO Calculation and Justification

The Maximum Allowable Carryover (MACO) is calculated using the PDE or ADE of the previous product to prevent cross-contamination and ensure patient safety.

1. Identify PDE/ADE: Retrieve the PDE or ADE value (µg/day) for the previous product manufactured on the equipment.
2. Calculate MACO (mg):
   
   MACO = (PDE or ADE x batch size of subsequent product) / [worst-case carryover volume or surface area]
   
   Example structure is:
   
MACO = (PDE µg/day × Batch size dose units) / 1,000,000 (to convert µg to mg)

3. Set Residue Limits: Based on MACO, define residue limits on surfaces and sampling areas.

Note: Site-specific inputs required include:

• Previous product’s PDE/ADE value
• Batch size (number of doses) of next product
• Sampling area dimensions ([swab_area_cm2])
• Analytical method limit of detection

Analytical Limits and Detergent Residue Criteria

Detergent residue limits will be based on validated analytical methods such as Total Organic Carbon (TOC) or specific detergent assays:

Detergent residue limits must be scientifically justified and based on toxicological thresholds. Analytical methods require validation for accuracy, specificity, precision, and LOD/LOQ.

Legacy Acceptance Limits (Fallback)

Where PDE/ADE data is unavailable, legacy rules may be applied as a conservative fallback:

• API carryover: less than 10 ppm related to the next product maximum daily dose
• Or less than 1/1,000th (0.1%) of the previous product’s therapeutic daily dose

This legacy approach must be clearly documented as fallback and phased out when PDE-based data becomes available.

Responsibilities

Safety and Personal Protective Equipment (PPE)

Safety is paramount during cleaning validation activities due to exposure risks associated with detergents, solvents, and residual drug substances. The following practices and PPE requirements must be strictly observed to safeguard personnel:

• Mandatory PPE: Chemical-resistant gloves, safety goggles or face shields, laboratory coats or disposable gowns, and appropriate respiratory protection if aerosols or volatile chemicals are used.
• Handling of Chemicals: Use Material Safety Data Sheet (MSDS) guidance for handling and disposal of detergents and cleaning agents. Avoid skin contact and inhalation.
• Machine Lockout/Tagout: Ensure equipment isolation procedures are followed before initiating cleaning to prevent accidental startup.
• Ventilation: Conduct cleaning operations in well-ventilated areas or under local exhaust ventilation to minimize inhalation risks.
• Training: Personnel must undergo training on safe handling of cleaning agents, PPE use, and emergency response for spills or exposures.

Equipment and Materials

Site-specific inputs required:

• Detergent name and concentration
• Rinse volume (L)
• Swab area (cm²) for each sampling location
• Analytical detection limits and methods

Hold Time Limits

To ensure cleaning effectiveness and to prevent residue hardening or microbial growth, hold time limits shall be established as follows:

Cleaning Validation Strategy Overview

This cleaning validation is designed around a risk-based approach utilizing PDE/ADE-based Maximum Allowable Carryover (MACO) principles for establishing acceptance criteria. The validation encompasses:

• Worst-case product selection based on toxicity, potency, and solubility.
• Use of validated analytical methods (TOC, HPLC, etc.) to detect product and detergent residues.
• Sampling at predetermined critical product-contact surfaces identified via risk assessment.
• Calculation of MACO values employing ADE or PDE with machine parameters and batch size considerations.
• Inclusion of legacy acceptance criteria (10 ppm or 1/1000 dose) only as fallback for non-toxic compounds.

Hard Gelatin Capsule Filling Machine Cleaning Procedure

1. Pre-Cleaning Preparation
   1. Ensure machine is stopped and isolated from power source.
   2. Remove bulk product residues from hopper, feed frames, and capsule handling areas using dedicated brushes and spatulas.
   3. Dispose of bulk residues per site’s waste management SOP.
   4. Document initial visual inspection of residues and condition of equipment before cleaning.
2. Disassembly
   1. Detach removable parts including capsule feeder, filling length adjuster, dosing discs, tamping pins, and shuttle assembly as per equipment manual.
   2. Place disassembled parts on clean stainless steel trays dedicated for cleaned parts.
   3. Keep small components in designated bins labeled with cleaning status to avoid cross-contamination.
   4. Record all disassembled parts with component ID and time of disassembly.
3. Cleaning – Wash Cycle
   1. Prepare [detergent_name] cleaning solution at recommended concentration in CIP or manual wash station.
   2. Immerse and brush all disassembled parts thoroughly targeting all product contact surfaces.
   3. Circulate detergent solution through non-removable piping and feed frame assembly if applicable.
   4. Maintain wash solution temperature at [temperature_°C] for optimum detergent performance.
   5. Allow a soak period of [soak_time_minutes] to loosen adherent residues.
   6. Document detergent lot number, concentration, temperature, and soak time.
4. Rinse Sequence
   1. Rinse all parts and fixed surfaces thoroughly using purified water at [water_temperature_°C].
   2. Use a minimum volume of [rinse_volume_L] per rinse cycle to ensure detergent removal.
   3. Perform multiple rinse cycles as specified until detergent residues fall below method detection limits.
   4. Where applicable, validate rinse water conductivity or TOC to confirm efficacy of rinse.
   5. Allow parts to drain and inspect for residual detergent or filler material presence visually.
5. Drying
   1. Dry parts using clean compressed air filtered through a 0.2 micron filter or by air drying in a controlled environment [temperature/humidity range].
   2. Ensure no visible moisture remains on surfaces before reassembly.
   3. Use lint-free cloths for wiping only when necessary, pre-sanitized per SOP.
6. Reassembly
   1. Reassemble cleaned parts onto the capsule filling machine as per the equipment manual.
   2. Ensure secure fitting of all components and lubricate with only approved lubricants where required.
   3. Record completion of reassembly and operator initials/signature.
7. Visual Inspection
   1. Perform a thorough visual inspection under adequate lighting for any residual product or detergent on all product contact surfaces including hopper, dosing discs, tamping pins, capsule guides, and filling chambers.
   2. Document visual inspection results and photograph critical surfaces if required.
   3. Release cleaned machine for sampling only if visual inspection passes.

Cleaning Process Parameters and Acceptance

Sampling Plan for Cleaning Validation

Sampling Technique and Documentation

1. Use validated swabbing material moistened with appropriate solvent (e.g., purified water, solvent recommended by assay).
2. For each location, swab defined area uniformly using a rolling motion to maximize residue recovery.
3. Use a new pair of gloves for each sampling location to prevent cross-contamination.
4. Immediately place swab into pre-labeled sterile container.
5. Document date, time, equipment ID, sampler initials, sample location, and any deviations in sampling logbook.
6. Maintain chain-of-custody form with signatures at every transfer point until laboratory receipt.
7. Samples forwarded to analytical laboratory under controlled environmental conditions, respecting hold time limits.

Site-Specific Inputs Required

• [detergent_name]
• [detergent_concentration]
• [temperature_°C] – wash temperature
• [soak_time_minutes]
• [rinse_water_temperature_°C]
• [rinse_volume_L]
• [swab_area_cm2]
• [max_particle_count] (if applicable)
• [max_hold_time_hours]

Sampling Plan and Locations

To ensure the cleaning effectiveness of the hard gelatin capsule filling machine, a comprehensive sampling plan must be established. Sampling locations represent critical points with high risk of product and detergent residue accumulation and serve as representative sites for evaluation.

• Sample site selections and total number must be justified based on risk assessment.
• Site-specific inputs required: swab_area_cm2, rinse volume, number of sampling points per location.

Analytical Methods for Residue and Microbial Detection

Chemical Residue Analysis

The following analytical methods are recommended to quantify residual product and detergent levels on the equipment after cleaning:

• Residual Active Ingredient Analysis: Use validated HPLC or UV spectrophotometric assays specific for the capsule filler’s product formulation.
• Detergent Residue Testing: Total Organic Carbon (TOC) – a universal and sensitive technique to detect organic detergent residues, preferred due to broad applicability across cleaning agents.
• Conductivity Measurement: Supplementary method for detergent residue confirmation, especially for ionic detergents.

All analytical methods must be validated per ICH Q2(R1) guidelines to ensure precision, accuracy, specificity, and sensitivity compatible with acceptance limits.

Microbial Limits (Risk-Based)

Microbial testing should be performed only if the cleaning validation is classified as high risk for bioburden contamination, such as subsequent sterile manufacturing or high microbial product risk. If applicable, utilize:

• Total aerobic microbial count (TAMC) per USP Microbial Examination of Nonsterile Products.
• Specification: ≤ 100 CFU/swab or rinse sample, adjusted based on risk assessment.

Acceptance Criteria and Rationale

Residue Limits on Equipment

Acceptance criteria are based on scientifically justified limits derived from the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) of the active pharmaceutical ingredient (API) combined with Maximum Allowable Carryover (MACO) calculations.

MACO Calculation:

MACO = (PDE or ADE × Batch size of next product) / Maximum batch size of previous product

where PDE/ADE is the permitted daily exposure for the API, considering toxicity data, and batch sizes are expressed in the same units (e.g., grams).

Residual acceptance limit: The residue per surface area should be less than or equal to the MACO adjusted for the sampled surface area to ensure carryover does not exceed safe levels.

Example Formula:

Acceptance Limit (µg/cm²) = (MACO in mg × 1000) / Total contact surface area (cm²)

Site-specific values for PDE/ADE, batch sizes, and surface areas are required for precise calculation.

Legacy approach: If PDE/ADE data are not available, the acceptance limit of 10 ppm or 1/1000th of the lowest therapeutic dose can be applied as a conservative fallback method. This must be explicitly stated as legacy and superseded by PDE/ADE data wherever possible.

Detergent Residue Acceptance

Detergent residues must be controlled and quantified using TOC or conductivity. Acceptance criteria should be set based on background levels measured during cleaning validation of residue-free equipment plus an established safety margin.

Example criteria:

• TOC levels ≤ [TOC_acceptance_limit] ppm
• Conductivity ≤ [conductivity_limit] µS/cm

Justification for limits should include method detection limits, detergent composition, and cleaning process specifics.

Microbial Limits (Optional)

If microbial testing is performed, limits should be established by risk assessment considering the subsequent product use and regulatory expectations.

Documentation and Records

• All cleaning validation activities including sampling, analysis, and acceptance decisions must be fully documented.
• Cleaning batch records should capture detergent lot, concentration, temperature, soak time, rinse volumes, and visual inspection outcomes.
• Sample logbooks should record exact sampling location, sample ID, operator name, and date/time.
• Analytical test reports must include raw data, calculations (PDE/ADE, MACO), and result interpretations.
• Any deviations or anomalies detected during validation must be investigated, documented, and addressed with corrective actions.

Analytical Method Performance: Recovery, LOD, and LOQ Expectations

For the cleaning validation of the hard gelatin capsule filling machine, analytical methods employed must demonstrate robust performance to ensure reliable detection and quantification of residues. Recovery studies should be conducted across representative surfaces of the equipment using defined matrices and artificial swab spiking to establish consistent analyte retrieval. Target recovery should be ≥ 80% to ensure confidence in the sampling and extraction procedures.

Limit of Detection (LOD) and Limit of Quantification (LOQ) must be determined for each residue analyte, including API, degradation products, and cleaning agents. The LOD should be sufficiently sensitive to identify residues at or below the established allowable residue levels, with a typical expectation of ≤ 0.1 µg/cm². LOQ levels are generally set at a value that provides acceptable precision and accuracy for quantification, preferably ≤ 0.3 µg/cm². These sensitivity parameters ensure that any potential contamination exceeding acceptance criteria can be reliably detected. Method validation reports substantiating these parameters must be available and referenced in the validation documentation.

Acceptance Criteria Methodology: PDE/ADE-Based MACO Approach

The primary acceptance criteria for residue limits on the hard gelatin capsule filling machine cleaning validation employ the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) based Maximum Allowable Carryover (MACO) approach. This scientifically justified risk-based method aligns with current regulatory expectations and surpasses legacy dose-based limits.

PDE/ADE Determination

The PDE or ADE values should be obtained from toxicological assessments for each Active Pharmaceutical Ingredient (API) processed on the equipment. These values reflect the maximum daily dose of an API to which a patient can be exposed without adverse effects.

MACO Calculation Structure

MACO (mg/cm²) Calculation:

MACO = (PDE or ADE) / (Maximum Daily Dose of Next Product × Surface Area)

This equation provides the maximum allowable residue per unit surface area to prevent cross-contamination.

Implementation Notes

• Site-specific inputs including [PDE_value], [MaxDose_next_product], [BatchSize], and [Equipment_Surface_Area_cm2] must be determined prior to validation.
• Worst-case product scenarios should be evaluated to ensure compliance even under conservative assumptions.
• Should PDE/ADE data be unavailable or insufficient, legacy acceptance limits may be applied with clear rationale.

Legacy Acceptance Limits (Fallback Only)

When toxicological data is not available, legacy acceptance criteria such as 10 ppm (10 parts per million) or 1/1000th of the therapeutic dose may be applied as provisional limits. These are not preferred but accepted if justified and documented as temporary measures. In this approach:

• 10 ppm limit equates to 10 µg of residue per gram of product.
• 1/1000th dose limit calculates acceptable residue as 0.1% of the therapeutic dose used in the next product.

Legacy limits should always be superseded by PDE/ADE-based MACO determinations when data becomes available.

Detergent Residue Acceptance Criteria and Rationale

The cleaning agent, [detergent_name], residues must be controlled to prevent interference with drug safety and efficacy. Detergent residue criteria shall be tied to an appropriate analytical technique such as Total Organic Carbon (TOC) analysis, conductivity measurement, or a specific assay for surfactants or critical detergent components.

Key justifications for detergent residue limits include:

• Analytical Justification: Use of TOC or conductivity allows quantifying total organic load or ionic contaminants with high sensitivity relevant to detergent components.
• Toxicological Safety: Detergent limits must be established based on toxicological evaluations, skin and mucosal irritation potential, and microbiological contamination risks.
• Process Capability: Limits are also set considering achievable process cleaning efficacy validated through recovery and swab studies.

As an example, TOC residue limits are typically established in the range of 10-20 µg/cm² after cleaning, though site-specific values must be assigned with rationale. Validation should confirm residue levels consistently fall below the defined acceptance criteria in the sampling locations outlined in Part B.

Deviation Management and Corrective & Preventive Actions (CAPA)

Any deviations observed during cleaning validation or routine cleaning operations must be documented with full root cause analysis. Examples of deviations include:

• Analytical results exceeding acceptance criteria.
• Failures in cleaning procedure adherence.
• Sampling or analytical method anomalies.
• Equipment malfunction affecting cleaning efficiency.

The CAPA process should include:

1. Identification and documentation of deviation details.
2. Root cause investigation describing the underlying issues.
3. Implementation of corrective measures such as procedure re-training, cleaning reagent or method adjustment, or equipment maintenance.
4. Preventive action plans to avoid recurrence, including enhanced monitoring or process improvement.
5. Documentation and review of CAPA effectiveness prior to revalidation or continued use.

All deviations and CAPAs must be recorded in compliance with GMP documentation standards and incorporated into ongoing cleaning validation records.

Continued Cleaning Verification Plan

To ensure sustained cleaning efficacy throughout routine production, a continued cleaning verification (CCV) plan must be implemented. The CCV program includes:

1. Periodic sampling and analytical testing based on the initial validated cleaning procedure and Sampling Plan defined in Part B.
2. Monitoring frequency determined by risk assessment, product changeover frequency, and process complexity, typically performed quarterly or biannually.
3. Documentation of sampling results against acceptance criteria consistent with PDE/ADE-based MACO limits.
4. Trend analysis to detect any drift or degradation in cleaning performance.
5. Triggering investigation and revalidation if trending data indicate increased residue levels or procedural noncompliance.

CCV ensures ongoing compliance with regulatory expectations and supports continuous improvement of cleaning processes.

Revalidation Triggers

Revalidation of the cleaning procedure for the hard gelatin capsule filling equipment is required under the following conditions:

• Change in Product or Formulation: Introduction of a new product with different API or excipient profile impacting residue risk.
• Modification of Equipment or Process: Physical changes to the capsule filling machine, ancillary equipment, or altered cleaning procedures.
• Process Failure or Deviation: Recurrence of cleaning failures, out-of-specification results, or CAPA indicating loss of control.
• Analytical Method Changes: Implementation of new methods that affect residue detection sensitivity or acceptance limits.
• Regulatory Updates: Changes in regional or global regulatory guidance affecting cleaning validation expectations.
• Time-Based Review: Scheduled periodic revalidation every 3-5 years as per site quality procedures.

Revalidation should be executed comprehensively with full documentation consistent with the original validation requirements.

Annexures and Templates

The following annexures and templates support the cleaning validation program and documentation for the hard gelatin capsule filling machine:

• Annexure A: Analytical Method Validation Report including recovery, LOD, LOQ, and specificity data.
• Annexure B: Risk Assessment Template to evaluate residue and microbial risks associated with product and equipment.
• Annexure C: MACO Calculation Worksheet with site-specific placeholders and examples.
• Annexure D: Cleaning Procedure Compliance Checklist to monitor adherence during routine operations.
• Annexure E: Sampling Log Template aligned with the Sampling Plan defined in Part B.
• Annexure F: CAPA Report Template tailored for cleaning validation deviations.
• Annexure G: Continued Cleaning Verification Schedule and Trend Analysis Form.

Use of these annexures ensures consistency, traceability, and regulatory compliance of the cleaning validation lifecycle and ongoing monitoring program.

Conclusion

The cleaning validation for the hard gelatin capsule filling machine must be governed by scientifically justified acceptance criteria based on PDE/ADE-derived MACO methodology to assure patient safety and product quality. Analytical method performance, including recovery, LOD, and LOQ, must be validated comprehensively to guarantee accurate residue quantification. Detergent residues require rational limits tied to relevant assay methods to prevent contamination risks. A robust deviation and CAPA framework alongside a continued verification plan ensures ongoing control and rapid response to anomalies. Revalidation is mandated upon critical changes or deviations to maintain validated status. The inclusion of detailed annexures and templates provides structured documentation and supports regulatory readiness. By adhering strictly to these governance principles, the cleaning validation lifecycle supports compliance with GMP and regulatory expectations for oral solid dosage manufacturing equipment.