Valve Crimping Machine Product Contact Interface Cleaning Validation Protocol and Procedure for Inhalation Dosage Forms

Purpose and Scope

The purpose of this document is to provide a structured cleaning validation protocol along with a corresponding cleaning procedure for the valve crimping machine’s product contact interfaces used in the manufacturing of inhalation dosage forms. This protocol ensures that the cleaning process is effective in removing product residues, cleaning agents, and potential contaminants to acceptable levels, ensuring patient safety and product quality.

This protocol applies specifically to valve crimping machines utilized in the pharmaceutical production of metered-dose inhalers (MDIs) and other inhalation products where the equipment’s product contact parts come into direct contact with the drug product or components thereof.

The scope covers:

• Identification of product contact parts of the valve crimping machine
• Cleaning agents and equipment used
• Overview of cleaning strategy including cleaning frequency and methods
• Hold times for dirty and cleaned equipment prior to use or release
• Roles and responsibilities for cleaning validation
• Safety and personal protective equipment (PPE) requirements during cleaning
• Documentation and record management related to cleaning activities and validation

Definitions and Abbreviations

Acceptance Criteria

The predetermined limits that residues must not exceed post-cleaning, based on toxicological and analytical data.

CIP

Cleaning In Place – automated cleaning of equipment without disassembly.

MACO

Maximum Allowable Carryover – the limit for residue transfer from one product batch to another.

PDE

Permitted Daily Exposure – the maximum acceptable intake of a contaminant per day.

TOC

Total Organic Carbon – measurement used to detect organic residues including detergents and product residues.

Swab Area

The defined surface area from which cleaning swabs are collected for residue analysis.

Valve Crimping Machine

A mechanical system that fixes a valve onto an inhaler canister by crimping.

Responsibilities

Safety and Personal Protective Equipment (PPE)

Personnel performing cleaning activities must adhere to the following safety and PPE requirements to protect themselves and ensure contamination control:

• Wear laboratory coats or cleanroom-approved garments suitable for production area
• Use disposable gloves resistant to cleaning agents used
• Eye protection (safety goggles or face shields) to prevent splashes from detergents or solvents
• Respiratory protection if volatile solvents or aerosols are involved in cleaning
• Closed-toe, nonslip safety footwear
• Follow Material Safety Data Sheets (MSDS) for all chemicals and detergents used

Emergency equipment such as eyewash stations and showers must be available and accessible during cleaning operations.

Equipment Overview and Product Contact Parts

The valve crimping machine is a key piece of equipment in assembling inhalation dosage forms, designed to affix valves securely onto canisters.

Critical product-contact interfaces requiring cleaning validation include:

• Valve crimping head or die
• Contact surfaces of the chuck or gripping mechanism
• Valve feeder channels or guide rails involved in valve handling
• Any seals or gaskets in direct contact with the valve or inhaler canister components
• Loading/unloading trays or nests that come into direct contact with product components

These parts must be clearly identified, traceable, and accessible for cleaning and sampling. Non-contact parts are excluded from validation but must not pose a contamination risk.

Cleaning Strategy Overview

The cleaning validation approach for the valve crimping machine consists of a risk-based, predetermined cleaning schedule and methodology to ensure robust removal of residues:

• Cleaning frequency: After every product batch change or at defined intervals based on risk assessment.
• Cleaning method: Combination of manual cleaning (disassembly, brushing, wiping) and cleaning in place (CIP) with appropriate detergents.
• Cleaning agents: Approved pharmaceutical-grade detergents with proven efficacy and low residue potential.
• Rinse procedures: Multiple rinses using purified water to remove detergent and residues, validated by TOC or equivalent methods.
• Hold times: Defined limits for dirty hold times prior to cleaning initiation to prevent residue hardening, and clean hold times before reuse to avoid contamination.
• Sampling methods: Swab sampling of defined product contact areas combined with rinse sampling where applicable.

Cleaning Agents and Tools

Definitions of Hold Times

Records and Forms

Documentation is essential to demonstrate cleaning validation compliance and ongoing control. The following records and forms should be maintained:

• Cleaning Procedure Log – documenting cleaning actions, personnel, times, and deviations
• Cleaning Validation Protocol – formal document outlining validation design and criteria
• Cleaning Validation Reports – including raw data, calculations, and final acceptance decisions
• Sampling Forms for swabs and rinse samples – detailing locations, times, and personnel
• Analytical Test Reports from QC – capturing testing methodology, results, and interpretations
• Preventive Maintenance Logs for valve crimping machine – ensuring equipment condition
• Material Safety Data Sheets (MSDS) for detergents and chemicals used

Site-specific Inputs Required

• Detergent name, concentration, and contact time ([detergent_name], [detergent_concentration], [contact_time_minutes])
• Rinse water volume and number of rinses ([rinse_volume_L], [rinse_number])
• Defined swab sampling areas in cm² ([swab_area_cm2])
• Dirty hold time limit for the valve crimping machine parts ([dirty_hold_time_hours])
• Clean hold time limit before reuse ([clean_hold_time_hours])
• Analytical methods available for detergent residue and product residue detection (e.g., TOC method name, specific assay)
• Maximum batch size and clinical daily dose for calculation of MACO based on PDE/ADE

Valve Crimping Machine Cleaning Procedure

1. Pre-Clean Preparation
   1. Ensure the valve crimping machine is powered off and isolated from any electrical source.
   2. Wear appropriate personal protective equipment (PPE): gloves, goggles, and protective gown.
   3. Remove all product residues visible on external surfaces with a clean, lint-free cloth dampened with purified water.
   4. Prepare cleaning agents and materials: [detergent_name], purified water, lint-free cloths, brushes compatible with product and materials of construction.
2. Disassembly of Product Contact Interfaces
   1. Disassemble all accessible and removable parts that come into contact with product or product residues, including but not limited to:
   • Valve crimping heads
   • Guides and alignment fixtures
   • Conveyor contact points
   2. Place disassembled parts into clean trays to avoid cross-contamination.
   3. Document part identification and location for reassembly purposes.
3. Cleaning Steps
   1. Manual Wash
      1. Apply [detergent_name] solution prepared as per manufacturer’s recommended concentration using brushes or lint-free cloths to all disassembled components and machine surfaces known for product contact.
      2. Allow detergent contact time per defined standard operating procedure (typically 10-15 minutes).
      3. Agitate difficult-to-clean areas with a soft brush to dislodge residues.
   2. Rinse
      1. Rinse all detergent-treated surfaces and parts thoroughly using purified water at minimum volume of [rinse_volume_L] per part/machine section to ensure removal of detergent residues.
      2. Repeat rinsing if any visible detergent residues or foaming are observed.
   3. Detergent Residue Control
      1. Perform conductivity or TOC swab sampling post-rinse to verify detergent residue removal as per analytical acceptance criteria.
4. Drying
   1. Dry all cleaned parts using a lint-free cloth or filtered compressed air to prevent microbial proliferation and corrosion.
   2. Allow air drying in a clean environment if tactile drying is impractical.
5. Reassembly
   1. Reassemble all cleaned parts in the reverse order of disassembly ensuring correct alignment and secure fixtures.
   2. Verify smooth operation of the valve crimping heads and other mechanical parts after reassembly.
6. Visual Inspection
   1. Inspect all product contact surfaces under adequate lighting to ensure absence of visible residues, discoloration, or damage.
   2. Record inspection results in the cleaning log for traceability.

Cleaning Parameters and Critical Control Points

Sampling Plan for Cleaning Validation

Sample Collection Methodology

1. Use sterile, pre-moistened swabs compatible with analytical methods (e.g., TOC or specific assay validation).
2. Swab the defined surface area with consistent swabbing technique ensuring uniform pressure and coverage.
3. After swabbing, immediately place the swab into sterile containers with proper labeling.
4. Record all relevant information (time, date, personnel, equipment ID) in the sample logbook and chain-of-custody form.
5. Maintain samples in appropriate conditions and deliver to the laboratory promptly to avoid degradation or contamination.

Sample Analysis Preparation

1. Prepare samples for analytical testing according to validated methods (TOC, conductivity, or specific residual assays).
2. Ensure samples are processed within [max_sample_hold_time_hours] hours of collection.
3. Document sample receipt and condition upon arrival at the laboratory.

Site-specific Inputs Required for Sampling Plan

• Swab area dimensions for each sampling location ([swab_area_cm2])
• Number of valve crimping heads and relevant components to be sampled
• Maximum permissible sample holding times before analysis ([max_sample_hold_time_hours])
• Analytical method method details and validation references for residue determination
• Chain-of-custody forms and documentation standards

Sampling Plan for Cleaning Validation

Sampling Locations

1. Valve crimping heads—critical contact surfaces in direct contact with product.
2. Guides and alignment fixtures adjacent to product flow.
3. Conveyor contact points where product residue accumulation is possible.
4. Internal crevices and hard-to-reach areas prone to residue retention.

Sampling sites are selected based on risk assessment considering product contact, residue accumulation potential, and cleaning difficulty.

Sampling Methodology

1. Swab Sampling: Use sterile swabs moistened with [swab_solvent] to collect residues from defined surface areas ([swab_area_cm2]) on all identified sites.
2. Rinse Sampling: Collect rinse water from defined machine sections during the final rinse step for detergent residue analysis.
3. Bulk Solution Sampling: If applicable, sample any recirculated cleaning solutions for residuals and microbial testing.

Sample Handling and Documentation

1. Label swabs and rinse samples clearly with location, date, and batch information.
2. Transport samples under controlled conditions to the analytical laboratory promptly.
3. Maintain chain of custody documentation and sample log sheets to ensure traceability.

Analytical Methods and Acceptance Criteria

Residue Limits Determination Using PDE/ADE-Based MACO

Cleaning acceptance limits for active pharmaceutical ingredients (APIs) and excipients will be derived using the PDE (Permitted Daily Exposure) or ADE (Acceptable Daily Exposure) approach, employing the Maximum Allowable Carryover (MACO) formula:

Site-specific inputs required for calculation:

• PDE or ADE value for all APIs involved
• Batch sizes for previous and subsequent products
• Surface area in contact with product for residue distribution

The MACO value will guide the maximum allowable residual contamination in the valve crimping machine interfaces.

Detergent Residue Limits

Detergent acceptance criteria will be tied to Total Organic Carbon (TOC) or conductivity measurement of rinse samples, with limits established per the following:

• TOC Limit: ≤ [TOC_limit_ppm]
• Conductivity Limit: ≤ [conductivity_limit_µS/cm]

These limits will be justified based on the detergent formulation, cleaning validation status, and risk assessment.

Microbial Limits (Risk-Based)

If microbial risk assessment indicates potential for microbial contamination post-cleaning, microbial limits shall be established according to USP Microbial Limits Tests, considering the product’s route of administration (inhalation) and associated sterility requirements:

• Total aerobic microbial count: ≤ [microbial_limit_TAMC] CFU/cm²
• Total yeast and mold count: ≤ [microbial_limit_YMC] CFU/cm²
• Absence of specified pathogens in 10 g or mL sample

Cleaning Validation Execution Steps

1. Perform initial cleaning as per Valve Crimping Machine Cleaning Procedure outlined previously.
2. Collect swab and rinse samples from all sampling sites immediately post-cleaning, before drying or reassembly.
3. Submit samples to the analytical laboratory for quantitative analysis of:
   • Residual API/excipients using validated HPLC or other specific methods.
   • Detergent residues utilizing TOC or conductivity methods.
   • Microbial contamination assessment if applicable.
4. Evaluate analytical results against acceptance criteria defined by the PDE/ADE-based MACO method and detergent residue limits.
5. Document all cleaning validation activities including deviations, corrective actions, and analytical data in the validation report.

Site-Specific Inputs Required

• [detergent_name]
• [rinse_volume_L]
• [swab_area_cm2]
• [swab_solvent]
• PDE or ADE values for all relevant APIs
• Batch size information for prior and subsequent product campaigns
• [TOC_limit_ppm]
• [conductivity_limit_µS/cm]
• [microbial_limit_TAMC]
• [microbial_limit_YMC]

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

For the valve crimping machine cleaning validation, the analytical methods employed for residue detection must demonstrate robust sensitivity and accuracy through defined recovery rates, limits of detection (LOD), and limits of quantification (LOQ). Recovery studies ensure that sampling techniques (e.g., swabbing, rinsing) effectively extract residues from product contact surfaces, while LOD and LOQ determine the minimum analyte amounts detectable and quantifiable, respectively.

Recovery Expectations: Recovery should ideally be ≥ 80% for swab and rinse sampling techniques across all product residues, including active pharmaceutical ingredients (APIs) and detergent residues. To establish this, recovery validation must be performed at multiple concentration levels representative of residual contamination range.

LOD and LOQ: The analytical method’s LOD must be sufficiently sensitive to detect residues at or below the Maximum Allowable Carry Over (MACO) levels calculated via PDE/ADE methodology. LOQ must be set such that quantification is achievable with acceptable accuracy (±20%) and precision (<15% relative standard deviation). Typical LOD and LOQ values will be site-specific and method-dependent but should always align with the MACO target levels.

All recovery, LOD, and LOQ data shall be documented in the method validation reports and reviewed during cleaning validation execution. These performance parameters ensure confidence in the residue quantification that underpins acceptance criteria decisions.

Acceptance Criteria Methodology: PDE/ADE-Based MACO Approach

The primary acceptance criteria for valve crimping machine cleaning validation will be derived using the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) toxicological approach combined with the Maximum Allowable Carry Over (MACO) framework. This methodology directly links cleaning requirements to patient safety by ensuring that residual cross-contamination remains below safe exposure limits.

Conceptual Overview

The PDE or ADE value represents the maximum amount of an API to which a patient can be safely exposed daily without adverse effects. Using PDE/ADE data, the MACO can be calculated and translated into acceptance criteria expressed in terms of residue mass or concentration on equipment surfaces.

Calculation Structure and Placeholders

Example: If PDE is 0.1 mg/day, max daily dose is 50 mg, batch size is 10,000 units, total contact surface is 1,000 cm², and swab area is 25 cm², then:

MACO = 0.1 × (10,000 / 50) = 20 mg

Limit per swab = (20 × 25) / 1,000 = 0.5 mg per swab area

Legacy Acceptance Criteria

As a fallback or during method establishment, legacy limits such as 10 ppm (parts per million) or 1/1000th of the clinical dose may be referenced. However, these shall only be used when PDE/ADE values are unavailable or as supplementary rationale. The PDE/ADE-based MACO methodology remains the gold standard for justification due to its direct toxicological basis.

Detergent Residue Acceptance Rationale

The valve crimping machine cleaning process employs [detergent_name] to ensure effective removal of fouling and residue. Acceptable limits for detergent residues are essential to avoid product contamination risks and maintain equipment integrity.

The detergent residue acceptance criteria will be based on the validated analytical method used, typically Total Organic Carbon (TOC), conductivity, or a detergent-specific assay such as colorimetric or HPLC-based detection.

Justification Principles

• TOC Measurement: TOC is widely regarded as a critical indicator for monitoring organic residues from detergents. Acceptance criteria shall be established based on the maximum allowable TOC contribution corresponding to [detergent_name] residues that do not pose risk of product contamination.
• Method Specificity: Where specific detergent assays are employed, limits must be aligned with toxicological or pharmacopeial data relevant to detergent components.
• Rinse Water Conductivity: For quick in-process checks, conductivity measurements provide an indirect but sensitive indication of residual ionic detergents and can be used in coordination with periodic TOC verification.

Example Acceptance Criterion:

TOC ≤ [TOC_limit_ppm], which corresponds to ≤ [detergent_name] residue of [detergent_residue_limit_mg/cm2] on the equipment surface.

Deviations and Corrective and Preventive Actions (CAPA)

Any deviations from the established cleaning validation acceptance criteria or procedures, including batch failures, incomplete cleaning cycles, or analytical out-of-specifications, shall trigger a formal deviation investigation according to Site Quality Management System protocols.

The CAPA process following a deviation must include:

1. Identification and documentation of root cause(s) (e.g., equipment malfunction, operator error, cleaning agent potency).
2. Immediate containment measures to prevent product impact.
3. Correction actions such as re-cleaning, re-sampling, or re-testing.
4. Preventive actions to mitigate recurrence, including staff retraining, procedure updates, equipment maintenance, or parameter adjustments.
5. Review and approval of CAPA by Quality Assurance and Validation representatives.
6. Documentation of all actions and outcomes in the deviation report and Cleaning Validation Master File.

Continued Verification Plan

Valve crimping machine cleaning validation shall be maintained over time through a rigorous continued verification program designed to ensure ongoing compliance and process robustness. Continued verification activities include:

Data from continued verification must feed into management reviews and trigger revalidation investigations as needed.

Revalidation Triggers

Revalidation of valve crimping machine cleaning is mandatory upon any of the following situations:

• Change in product formulation or patient dose that affects PDE/ADE or residue characteristics
• Material or process changes involving detergents, cleaning parameters, or machine modifications
• Change in equipment design, component repair, or replacement of critical product contact parts
• Significant or repeated deviations or out-of-specification results observed during cleaning validation or routine monitoring
• Regulatory agency requests or updated guidance requiring reassessment
• Unexpected microbiological contamination associated with cleaning failure risks
• Expansion of the manufacturing scope or inclusion of a new product that requires assessment

Revalidation protocols shall be developed with reference to prior successful validations, ensuring thorough evaluation of the changes and impacts, including sampling and analytical verification per the validated methods.

Annexures and Templates

Supporting annexures and templates relevant for valve crimping machine cleaning validation shall be included and aligned to site documentation control practices:

• Annexure A: Analytical Method Validation Summary Reports for Residue and Detergent Testing
• Annexure B: Cleaning Validation Recovery Study Protocol and Results
• Annexure C: Sampling Plan Template (See reference in Part B)
• Annexure D: Cleaning Procedure and Equipment Specification Details
• Annexure E: Calculation Worksheets for PDE/ADE MACO and Residue Limits
• Annexure F: Deviation and CAPA Report Form Template for Cleaning Validation Incidents
• Annexure G: Continued Verification Schedule and Monitoring Checklist

These annexures facilitate standardized documentation, audit readiness, and streamlined review cycles.

Acceptance Criteria for Residual API

The acceptance criteria for residual active pharmaceutical ingredient (API) carryover on the valve crimping machine product contact surfaces shall be established based on the PDE/ADE-based Maximum Allowable Carry Over (MACO) methodology as follows:

The acceptance criterion for each swab sample is the MACO value adjusted proportionally for the sampled swabbed area. Residues detected above this limit indicate insufficient cleaning.

Acceptance Criteria for Detergent Residue

Detergent residue acceptance criteria shall be determined based on analytical results obtained via validated Total Organic Carbon (TOC) analysis or appropriate specific detergent assays. The protocol requires:

• The TOC limit shall be set to not exceed [TOC_limit_ppm], which reflects the maximum allowed detergent residue.
• When specific detergent assays are used, the limit should correspond to the threshold limit of the active detergent component established by toxicological evaluation.
• Conductivity or other indirect methods may be used for routine monitoring but must be correlated with TOC or specific assay data.

Residual detergent levels must be below the established limits to prevent product contamination and incompatibility issues.

Microbial Acceptance Criteria (Risk-Based)

Given the valve crimping machine’s product contact surfaces and the non-sterile nature of inhalation dosage forms, microbial limits are applied strictly based on risk assessment as follows:

Sampling methodology and analytical techniques must be validated to reliably detect microbial contaminants at these limits.

Acceptance Criteria Fallback: Legacy Limits

In cases where PDE/ADE data are unavailable or undeveloped for the API, legacy acceptance criteria may be applied as a fallback approach with explicit documentation, including:

• API retention limit of 10 ppm (parts per million) on cleaned surfaces
• Alternatively, a limit of 1/1000 of the lowest therapeutic dose administered per batch

Legacy criteria shall be replaced by PDE/ADE-based criteria as soon as sufficient data permit.

Data Evaluation and Reporting

1. Compile all residue test results per the Sampling Plan defined in Part B, including swab and rinse samples.
2. Calculate residue levels using the predefined acceptance limit calculations and compare with MACO or detergent limits.
3. Evaluate recovery and LOD/LOQ validation data to ensure analytical reliability for all tested residues.
4. Tabulate microbial bioburden results and validate conformance to microbial acceptance criteria where applicable.
5. Identify and investigate any out-of-specification (OOS) findings; initiate corrective and preventive actions (CAPA) if required.
6. Prepare a comprehensive Cleaning Validation Report incorporating data synthesis, deviations, re-testing outcomes, and conclusion statements.

Site-Specific Inputs Required

• [PDE_value_mg_per_day]: Acceptable Daily Exposure for the product API
• [Batch_size_units]: Maximum batch size for cleaning scope
• [Surface_area_cm2]: Total product contact surface area subject to cleaning
• [swab_area_cm2]: Area sampled per swab
• [TOC_limit_ppm]: Total Organic Carbon limit for detergent residue
• [detergent_name]: Detergent product used in cleaning
• [rinse_volume_L]: Volume of water used for final rinsing steps

Acceptance Criteria for Valve Crimping Machine Cleaning Validation

Primary Acceptance Criteria Based on PDE/ADE-Derived MACO

The cleaning validation acceptance criteria for all product residues on valve crimping machine product contact interfaces shall be established using the PDE (Permitted Daily Exposure) or ADE (Acceptable Daily Exposure) approach. This risk-based methodology ensures patient safety by controlling cross-contamination within toxicological limits.

MACO Calculation Equation:

MACO (μg/cm²) = (PDE or ADE × Acceptable Daily Dose of Next Product) ÷ Surface Area ÷ Recovery Factor

All detected residual API levels must be below calculated MACO limits. If multiple APIs or detergents are involved, criteria apply individually or cumulatively based on risk assessment.

Acceptance Criteria for Cleaning Agent Residues

Detergent residues shall be controlled based on analytical detection using Total Organic Carbon (TOC) or a validated specific assay method. The acceptance limits should ensure no interference with product quality and patient safety.

Limits must be justified via risk-based assessment and supported by cleaning process capability data.

Microbial Limits (If Applicable)

Microbial acceptance criteria should be applied only if risk assessment classifies the valve crimping machine as a microbial hazard for the next product. In such cases, limits should be aligned with product risk profiles and GMP guidelines:

Legacy Acceptance Criteria for Reference Only

The legacy acceptable limits of 10 ppm or 1/1000 of the minimum therapeutic dose may be applied only as fallback criteria when PDE/ADE data are unavailable. Note that these criteria lack toxicological risk correlation and are superseded by PDE/ADE-based criteria whenever possible.

Re-Validation and Change Control Criteria

Cleaning validation shall be re-assessed and re-validated under the following conditions to ensure sustained control of residues:

1. Change in product formulation or API potency that affects PDE/ADE values.
2. Modification of the valve crimping machine design or product contact parts.
3. Changes in detergent/cleaning agents or cleaning procedure parameters.
4. Failures observed in routine monitoring or trending indicating loss of cleaning effectiveness.
5. Periodic requalification as part of ongoing GMP compliance (recommended every 2-3 years or per site practice).

Change controls must include updated risk assessments and, if necessary, expanded cleaning validation experiments or sampling.

Data Analysis and Reporting

All residue analysis results must be compiled and compared against acceptance criteria defined above.

1. Document actual recovery percentages achieved in sample analyses and verify conformance to validated recovery levels.
2. Calculate residual amounts detected and express results normalized per surface unit (e.g., µg/cm²).
3. Compare measured residues against MACO limits; any excursion requires investigation and corrective actions.
4. Include detergent residues and microbiological results as applicable, with reference to validated methods and limits.
5. Summarize findings in a comprehensive Cleaning Validation Report, highlighting compliance or deviation.

Acceptance Criteria for Residual Drug Substances

PDE/ADE-Based MACO Calculation Methodology

The Maximum Allowable Carry Over (MACO) for the valve crimping machine’s product contact surfaces shall be calculated based on the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) values of the respective APIs. The MACO limits the residual amount of API permissible to remain post-cleaning, assuring patient safety and compliance with regulatory expectations.

The MACO calculation is as follows:

Example calculation and complete data inputs must be documented site-specifically.

Legacy Acceptance Criteria (Fallback)

Where PDE/ADE data is unavailable, legacy acceptance criteria may apply as a fallback:

• Residual API limit: ≤ 10 ppm (mg/kg) or ≤ 1/1000 of the minimum therapeutic dose per surface area.
• Detergent residues: no visible residues and below established TOC limits.

Note: Legacy criteria must be clearly marked as such in documentation and replaced with PDE/ADE approach when possible.

Acceptance Criteria for Detergent Residues

Analytical Method and Limits

Detergent residues must be assessed using validated Total Organic Carbon (TOC) analysis or a detergent-specific assay method (e.g., HPLC, conductivity measurement), depending on the detergent employed.

Site-specific cleaning agents and their detection methods shall be documented, including validated acceptance criteria matching the chosen analytical technique.

Microbiological Limits (If Applicable)

A risk-based assessment determines microbiological control on the valve crimping machine’s product contact surfaces. If the process or product is susceptible to microbiological contamination, the following limits and methods apply:

• Total aerobic microbial count (TAMC): ≤ [TAMC_limit] CFU/cm²
• Total yeast and mold count (TYMC): ≤ [TYMC_limit] CFU/cm²
• Pathogen exclusion (e.g., absence of Salmonella, E. coli): Mandatory

Sampling follows the defined Sampling Plan with validated microbiological methods (e.g., RODAC plates, membrane filtration).

Data Evaluation and Reporting Criteria

1. All sampling data must demonstrate residue levels below established MACO and detergent limits to confirm cleaning effectiveness.
2. Analytical method validation documentation supporting recovery, LOD, and LOQ compliance must be appended.
3. Out-of-specification results require re-cleaning, resampling, and root cause investigation per site SOPs.
4. Acceptance criteria shall be met consistently over minimum [number_of_batches] consecutive validation batches before routine monitoring.
5. All data shall be documented precisely in validation reports with traceability to equipment, batch, sampling, and analysis.

Acceptance Criteria for Residual Active Pharmaceutical Ingredients (APIs)

The acceptance criteria for residual APIs on the valve crimping machine’s product contact surfaces shall be based on PDE/ADE-derived Maximum Allowable Carry Over (MACO) limits to ensure patient safety and compliance with regulatory guidelines.

PDE/ADE-Based MACO Calculation

The MACO for each residue is calculated using the formula:

MACO (mg) = PDE × Batch Size / Lowest Daily Dose

• PDE: Permitted Daily Exposure (mg/day), derived from toxicological data.
• Batch Size: Quantity of drug product manufactured in a single batch.
• Lowest Daily Dose: The smallest dose administered to patients for the prior product processed on the equipment.

The MACO value is then converted to a surface residue limit based on the total cleaned surface area:

Acceptance Limit (μg/cm²) = (MACO (μg)) / Total Product Contact Surface Area (cm²)

Implementation of MACO Limits

• Residual API levels must be ≤ calculated MACO limit on all sampled product contact surfaces.
• Results exceeding MACO limits will require re-cleaning and possible investigation.
• PDE values and batch sizes must be documented as part of validation records.

Legacy Acceptance Limits (Fallback)

Where PDE data is unavailable, legacy limits may be used:

• 10 ppm (mg API/kg equipment surface) as a maximum residue level.
• Or 1/1000th of the lowest therapeutic dose per equipment surface area.
• Use of legacy limits must be justified and risk-assessed in documentation.

Acceptance Criteria for Detergent Residues

Detergent residues shall be controlled to levels that pose no risk to product quality or patient safety. Analytical measurement will be tied to validated methods such as Total Organic Carbon (TOC), conductivity, or a detergent-specific assay.

Analytical Method Justification

• TOC analysis: Used for non-specific organic residues. Limits based on method sensitivity and cleaning chemistry.
• Conductivity: Applied where ionic detergents are used, with limits based on baseline rinse water and cleaning cycle parameters.
• Specific Detergent Assays: Employed where applicable for critical detergent components (e.g., surfactants).

Detergent Residue Limits

Site-specific inputs required: [TOC_limit_ppm], [conductivity_limit_µS/cm], [specific_assay_limit]

Microbial Limits and Rationale

Cleaning validation for the valve crimping machine focuses primarily on chemical residue control. Microbial limits shall be applied only if risk assessment identifies potential microbiological contamination risks linked to the cleaning process or product.

• If applicable, microbial limits must follow risk-based acceptance criteria aligned with the product requirements (e.g., ≤ 100 CFU/cm²)
• Validation sampling shall include bioburden testing of cleaned surfaces and rinse waters where relevant.
• Procedures and limits must be justified and validated per GMP standards.

Data Analysis and Reporting

Analytical data generated through the sampling plan defined in Part B shall be reviewed for compliance with the acceptance criteria. Key activities include:

1. Verification that all sample results are within specified MACO limits for APIs and detergent residue limits.
2. Calculating recovery efficiencies and adjusting results accordingly.
3. Documenting any deviations, investigations, and corrective actions taken.
4. Compiling a comprehensive validation report summarizing methodology, results, and conclusions.

Conclusion

Acceptance criteria established through PDE/ADE-based MACO limits, complemented by determinant detergent residue limits and risk-based microbial controls, provide a scientifically justified framework to confirm the effectiveness of the cleaning process for the valve crimping machine product contact interfaces. Compliance with these criteria ensures validated control of cross-contamination and supports GMP requirements for inhalation dosage form manufacturing.