Cleaning Validation Protocol and Procedure for High-Speed Stirrer Wetted Components in Liquid Oral Dosage Manufacturing

Purpose and Scope

This document establishes a robust cleaning validation protocol and standard operating procedure (SOP) tailored for the wetted parts of high-speed stirrers utilized in the manufacturing of liquid oral dosage forms within pharmaceutical production. The protocol is specifically designed to ensure that cleaning procedures are effective in removing product residues, cleaning agents, and microbial contaminants to a level compliant with regulatory expectations and internal quality standards.

Scope encompasses validation activities including cleaning process definition, sampling strategies, acceptance criteria setting, cleaning agent selection, and documentation requirements related exclusively to the wetted parts of high-speed stirrers. This excludes non-product-contact parts unless they pose a contamination risk. The protocol supports qualification activities during commissioning, routine cleaning validation campaigns, and change control scenarios impacting cleaning efficacy.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

Given the handling of cleaning chemicals, potentially contaminated equipment parts, and sampling activities, all personnel involved must adhere to established safety guidelines and wear appropriate PPE.

• Protective gloves resistant to cleaning agents (e.g., nitrile gloves)
• Safety goggles or face shield to prevent splashes to eyes
• Laboratory coats or disposable gowns
• Closed-toe, non-slip footwear
• Respiratory protection as mandated by Material Safety Data Sheets (MSDS) for cleaning agents
• Proper training on chemical hazards and emergency procedures

Local site-specific requirements must be followed, including use of eye wash stations, safety showers, and spill containment measures.

Equipment Overview and Product-Contact Parts

The high-speed stirrer system under validation is typically comprised of the following main components:

• Impeller blades: Stainless steel or Hastelloy blades rotating at high RPM for mixing
• Central drive shaft: Connects the impeller to the motor, transmitting rotational force
• Seal assembly: Mechanical or lip seals preventing leakage of product and cleaning fluids
• Stirrer housing/contact chamber: Enclosure or tank where stirring occurs, product-contact surfaces polished or electropolished for cleanability
• Mounting fixtures and fasteners: Product-contact elements including clamps, gaskets made from regulatory-compliant materials

All wetted parts must be manufactured from materials compliant with relevant pharmacopoeial standards and exhibit adequate surface finish to allow effective cleaning and residue removal. Special attention will be paid to crevices, joints, and seal interfaces where residues could accumulate.

Cleaning Strategy Overview

The cleaning approach focuses on maximizing residue removal through a combination of mechanical, chemical, and rinsing actions:

• Disassembly (if applicable): Depending on equipment design, partial dismantling of wetted parts to ensure access for cleaning and inspection
• Manual cleaning: Removal of bulk residues and visible soil with brushes, scrapers, or wipes using a targeted detergent solution
• Automated cleaning step (if available): Circulation of detergent solution at controlled temperature or ultrasonic cleaning for enhanced removal
• Rinsing: Multiple rinses with purified water to eliminate residual detergent and loosened soil
• Drying: Air or inert gas drying to prevent microbiological growth during post-cleaning hold
• Sampling: Defined swabbing and rinse sampling locations based on risk assessment and product-contact geometry

Hold time controls will be implemented to prevent residue hardening or microbial proliferation after production and after cleaning completion.

Cleaning Agents and Tools List

Hold Times Definitions

Hold times shall be defined based on microbial risk assessment, residue chemistry, and operational practicality. Confirmations via stability or microbiological studies may be required.

Records and Forms List

• Cleaning Validation Protocol and Report
• Cleaning Procedure (SOP) Document
• Cleaning Batch Records: Documentation of executed cleaning steps and parameters
• Sampling and Testing Records: Log sheets for swabbing, rinsing, and analytical testing data
• Equipment Cleaning Logs: Date/time and personnel records for cleaning activities
• Hold Time Monitoring Records
• Deviation and CAPA Forms: Recording any irregularities and corrective actions related to cleaning
• Training Records: Personnel qualification and refresher training related to cleaning procedures
• Analytical Method Validation Documentation (for residue and detergent detection methods)

Site-Specific Inputs Required

• [detergent_name]: Full chemical name, concentration, and supplier details of the cleaning agent used
• [rinse_volume_L]: Defined wipe and rinse volumes for samples and final rinses
• [swab_area_cm2]: Specific sampling areas for swab/pad recovery to standardize residue measurements
• [max_dirty_hold_hours]: Maximum time limit allowed between manufacturing end and cleaning start
• [max_clean_hold_hours]: Maximum time permitted between cleaning completion and equipment use
• List of high-speed stirrer wetted part materials and surface finish parameters
• Detailed drawings or photographs for precise sampling location identification
• Analytical methods employed for residue detection (e.g., TOC, HPLC, Conductivity) with validation status
• Microbial limit acceptance criteria, if applicable, based on specific risk assessments

Cleaning Procedure for High-Speed Stirrer (Wetted Parts)

1. Pre-Cleaning Preparation
   1. Ensure the high-speed stirrer is turned off and disconnected from power sources.
   2. Wear appropriate personal protective equipment (PPE) including gloves, goggles, and lab coats.
   3. Prepare all cleaning materials and detergents as per the Manufacturer’s Safety Data Sheet (MSDS). Use designated cleaning area compliant with GMP standards.
   4. Document batch number, cleaning date, and operator name in the cleaning log.
2. Disassembly of Wetted Parts
   1. Carefully disassemble the high-speed stirrer’s wetted parts (shaft, blades, seal, and any other components that contact the product) as per equipment-specific SOP.
   2. Inspect parts for visible damage or wear and report any anomalies to Engineering/Maintenance.
   3. Place disassembled parts on a clean, sanitized surface ready for cleaning.
3. Washing Process
   1. Prepare detergent solution using [detergent_name] at the recommended concentration and temperature (typically 40-60°C). Site-specific inputs required.
   2. Submerge wetted parts completely in the detergent solution ensuring full contact with all surfaces.
   3. Use a soft brush or sponge to scrub all parts thoroughly, paying special attention to hard-to-reach crevices and seals.
   4. Operate an ultrasonic cleaner with detergent solution for [ultrasonic_duration_minutes] minutes if applicable to enhance cleaning efficiency.
4. Rinse Sequence
   1. Rinse each wetted part thoroughly with potable water initially to remove bulk detergent residues.
   2. Follow with a second rinse using purified water with a minimum volume of [rinse_volume_L] per part to eliminate residual detergent and product.
   3. Optionally perform a final rinse with water-for-injection (WFI), if required by product criticality.
5. Drying
   1. Dry parts using lint-free cloths or compressed filtered air (filtered to 0.22 μm) to avoid microbial contamination thereafter.
   2. Ensure no moisture is retained in crevices or seals that might promote microbial growth or product degradation.
6. Reassembly
   1. Reassemble the wetted parts carefully according to equipment manuals and SOP instructions.
   2. Confirm all seals and fittings are properly positioned and secured to prevent leaks during operation.
7. Visual Inspection
   1. Conduct thorough visual inspections of reassembled wetted parts to confirm cleanliness and absence of residual product, detergent residues, discoloration, or damage.
   2. Document findings and take photographic evidence where applicable.

Cleaning Process Parameters

Sampling Plan for Cleaning Validation of High-Speed Stirrer Wetted Parts

Sampling Methodology

1. Use pre-moistened, validated swabs suitable for residue recovery of both product and detergent residues.
2. Swab uniform square areas of [swab_area_cm2] per location using appropriate swabbing pattern (horizontal then vertical strokes) to maximize residue pickup.
3. Label samples immediately with unique identifiers; sample labels to include equipment ID, sampling location, date, time, and operator.
4. Maintain thorough chain-of-custody logs for all samples from collection through laboratory receipt and analysis.
5. Store swab samples under controlled temperature (2-8°C) and transport to analytical laboratory within [sample_transport_time] hours.
6. Submit samples for analysis using validated methods such as TOC for detergent residues, HPLC or UV assay for product residues, and conductivity for rinse water verification as applicable.
7. Ensure sampling personnel are trained and qualified in aseptic techniques and sampling procedures.

Site-Specific Inputs Required

• [detergent_name] — detergent brand and type used for cleaning.
• [detergent_conc] — recommended detergent concentration (% w/v).
• [ultrasonic_duration_minutes] — duration for ultrasonic cleaning, if applied.
• [rinse_volume_L] — volume of rinse water applied per part during rinse.
• [swab_area_cm2] — defined swab sample surface area (usually 25-100 cm²).
• [sample_transport_time] — maximum allowable time from sampling to lab receipt (in hours).

Sampling Plan for High-Speed Stirrer (Wetted Parts)

Sampling is a critical component of cleaning validation and must be designed to adequately represent the cleanliness of the wetted parts’ surfaces.

Sampling Locations

• Blade surfaces (both sides)
• Shaft surface
• Seal interfaces
• Areas prone to product or detergent accumulation such as crevices and joints

Site-specific inputs required: swab_area_cm2 for each sampling location.

Sampling Methodology

1. Use validated sampling tools such as sterile swabs or rinse collection devices suitable for detecting the target residues.
2. Swabbing should be done using suitable solvent (e.g., purified water or specific extraction solvent) to recover residues effectively.
3. Ensure consistent pressure and technique across sampling sites, covering entire swab area.
4. Label samples clearly with equipment ID, sampling location, date, and operator initials.
5. Immediately transport samples to the QA/QC laboratory under appropriate conditions to avoid degradation.

Analytical Methods for Residue Detection

Detergent Residue Analysis

Product Residue Analysis

Analytical methods should detect residual active pharmaceutical ingredient (API) or excipients relevant to the oral liquid product. Analytical methods may include:

• HPLC with UV or MS detection tailored to product’s API
• UV-Vis spectroscopy for relevant excipients
• Other validated quantitative assays as per product specifications

Acceptance Criteria and Thresholds

PDE/ADE-Based Maximum Allowable Carry Over (MACO) Calculation

The acceptance criteria for residual product are calculated based on toxicological PDE (Permitted Daily Exposure) or ADE (Acceptable Daily Exposure) data using following formula:

Site-specific inputs required:

• PDE or ADE value for API or excipients of the previous product
• Maximum daily dose of previous product (product cleaned from)
• Maximum daily dose of next product (product manufactured after cleaning)

The MACO value defines the maximum acceptable residue allowable to be carried over without risk to patient safety.

Acceptance Limits for Detergent Residues

Detergent residues must not exceed limits determined by the cleaning verification method:

• For TOC: Residual TOC concentration must be below [TOC_limit_ppm] ppm, based on background contamination levels and method sensitivity.
• For Conductivity: Conductivity must be within [conductivity_limit_μS/cm] microSiemens/cm as per validated standard.
• For specific detergents: Residual concentration must be below method LOQ or a defined toxicological threshold.

These limits are established through method validation and risk assessment.

Legacy Acceptance Criteria (If PDE/ADE Data Unavailable)

When PDE/ADE data is unavailable, legacy criteria may be applied as a fallback method:

• Product Residue Limits: ≤ 10 ppm (0.001% w/w of product dose)
• Detergent Residue Limits: ≤ 10 ppm by TOC or appropriate specific assay

However, it is highly recommended to adopt PDE/ADE-based MACO to ensure a scientifically robust safety margin.

Microbial Limits (Risk-Based Application)

Microbial testing of wetted parts surfaces should be considered only if the cleaning validation is for products or processes where microbiological contamination presents a significant risk (e.g., sterile liquids, sensitive oral formulations).

• Acceptance Criteria: Total aerobic microbial count ≤ [microbial_limit_cfu] CFU/cm²
• Absence of objectionable pathogens (e.g., Staphylococcus aureus, Salmonella spp.)

Sampling and testing methodologies must align with pharmacopeial or company standards.

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

In establishing the validation parameters for the high-speed stirrer cleaning process, it is critical to evaluate and justify the method’s sensitivity and robustness through recovery studies, LOD, and LOQ determinations. These parameters verify the ability of analytical methods, such as TOC, conductivity, or specific detergent assays, to detect and quantify residues at relevant levels with acceptable accuracy and precision.

Recovery Studies: Recovery experiments must be performed by spiking known quantities of the drug product residues and cleaning agent residues onto the high-speed stirrer wetted parts or representative surfaces. Recovery should consistently fall within 80–120% to ensure method reliability in reflecting true residue levels, accounting for matrix effects inherent to the equipment surfaces.

LOD and LOQ Determination: The LOD identifies the smallest quantity of residue that can be confidently detected, whereas the LOQ is the smallest quantity that can be quantifiably measured with acceptable precision (typically relative standard deviation (RSD) ≤20%). The LOD and LOQ should be well below the acceptance limits derived from the PDE/ADE-based acceptance criteria model to guarantee method suitability. For TOC and conductivity methods, instrument-specific detection capabilities must be documented.

• Site-specific inputs required:
  • [recovery_percentage_threshold]
  • [LOD_value_method_specific]
  • [LOQ_value_method_specific]

Acceptance Criteria Methodology: PDE/ADE-Based MACO Approach

The acceptance criteria for residual drug substance on the high-speed stirrer wetted parts are established using the PDE (Permitted Daily Exposure) or ADE (Acceptable Daily Exposure) based Maximum Allowable Carryover (MACO) calculation methodology. This approach offers a scientifically justified and risk-based limit founded on patient safety considerations.

MACO Calculation Structure:

The MACO limit is then translated into an analytical concentration limit based on the sample collection strategy. For swab/swabbed area-based sampling:

Acceptance Limit (mg/cm²) = MACO / (Swabbed Surface Area [cm²] x Recovery)

Where recovery is expressed as a decimal fraction (e.g., 0.85 for 85% recovery).

Example: For a PDE of 5 µg/day, batch size of 1000 L, next product MDD of 500 mg, rinse volume of 5 L, swab area of 100 cm², and recovery of 0.9, the MACO limit and acceptance criteria are calculated accordingly to ensure safety.

Legacy Acceptance Criteria (Fallback): In absence of ADE/PDE values, a conservative approach using either 10 ppm or 1/1000th of the therapeutic daily dose can be applied as an interim control level, clearly demarcated as legacy and subject to replacement once toxicology data becomes available.

Detergent Residue Rationale

The detergent residue acceptance criterion must align with validated analytical methods specific to the detergent used on the high-speed stirrer wetted parts. The choice of analytical strategy (e.g., TOC, conductivity, or detergent-specific assays like HPLC for surfactants) is driven by the detergent’s chemical nature and detection feasibility.

Justification Framework:

• Detergent material composition and toxicity profile reference must support PDE-style limits or otherwise demonstrate extremely low safety risks.
• TOC is frequently used when the detergent contains organic components amenable to carbon detection; method must differentiate organic carbon from drug residues.
• Conductivity measurements serve for ionic detergents providing rapid rinse water quality checks, but require baseline and limit definition based on site-specific rinse studies.
• Specific assays for key detergent components support precise quantification where applicable.
• Acceptance limits shall be set based on rinse water quality objectives, e.g., less than [detergent_residue_limit] mg/L, backed by toxicological data or technical rationale.

Site-specific inputs required:

• [detergent_name]
• [detergent_residue_limit]
• [analytical_method]

This rationale underpins that residual detergents do not compromise product quality, process safety, or patient wellbeing.

Deviations and Corrective and Preventive Actions (CAPA)

Any deviations observed during the execution of the cleaning validation or routine verification phases must be documented and investigated thoroughly to identify root causes and implement corrective and preventive actions.

• Deviation Examples: Residuals exceeding acceptance criteria, incomplete cleaning documented during swabbing, failure of analytical equipment or method performance issues.
• Investigation: Root cause analyses will consider process parameters, operator interventions, detergent efficacy, sampling technique deficiencies, or equipment malfunction.
• CAPA Actions:
  1. Re-cleaning and re-sampling of affected equipment.
  2. Adjustment or optimization of cleaning procedure parameters such as detergent concentration, cleaning time, temperature, or rinse volumes.
  3. Retraining of personnel involved in cleaning execution and sampling.
  4. Analytical method review or revalidation if method-related issues are identified.
  5. Equipment maintenance or repair if mechanical factors are contributing causes.
• Deviations and CAPAs shall be reviewed and approved through quality management systems with documented closure and efficacy check.

Continued Verification Plan

Post-validation, to ensure ongoing control of cleaning process performance, a documented Continued Verification Plan shall be established. This plan is risk-based and may include periodic re-assessment as follows:

• Sampling Frequency: Routine sampling of the high-speed stirrer wetted parts post-cleaning in production or during scheduled maintenance, e.g., quarterly or semi-annually.
• Parameter Monitoring: Monitor critical process parameters including detergent concentration, cleaning time, temperature, and rinse volumes to ensure compliance with validated process conditions.
• Analytical Monitoring: Ongoing analytical verification of residues using the validated methods with trending to identify potential process drift or degradation in cleaning quality.
• Documentation: All results are recorded and reviewed during management quality reviews with escalation of exceptions.
• Risk-Based Adjustments: Continued verification frequency and scope shall be adjusted based on historical data, changes in product, process or regulatory expectations.

Revalidation Triggers

Cleaning procedure revalidation shall be performed whenever significant changes or events occur that may impact cleanliness. Triggers include but are not limited to:

• Change in drug substance formulation that affects residue characteristics or solubility.
• Modification of the high-speed stirrer equipment design or wetted parts.
• Change in detergent type, concentration, or cleaning process parameters.
• Repeated deviations or CAPA outcomes indicating process inadequacies.
• Regulatory or quality system findings necessitating reassessment.
• Introduction of new target products with different PDE/ADE values requiring updated MACO calculations.

Each revalidation shall include review of critical process parameters, updated cleaning validation sampling and analytical testing according to established protocols.

Annexures and Templates

To support the implementation and documentation of cleaning validation for the high-speed stirrer wetted parts, the following Annexures and Templates shall be maintained and controlled under document management systems:

Conclusion

The cleaning validation of the high-speed stirrer wetted parts relies on a robust and scientifically justified approach using PDE/ADE-based MACO methodology to define residue acceptance criteria, thereby prioritizing patient safety and regulatory compliance. Strategic recovery studies, sensitivity assessments (LOD/LOQ), and rational detergent residue limits ensure the analytical methods reliably detect residues within acceptable thresholds. The protocol provides a clear framework for deviations management, ongoing process verification, and revalidation triggers, fostering continuous maintenance of cleaning efficacy and equipment hygiene. Comprehensive annexures and templates underpin meticulous documentation and audit readiness. Adherence to this validation governance framework guarantees consistent cleaning performance supporting high-quality pharmaceutical manufacture of liquid oral dosages.