Oscillating Granulator Cleaning Validation Protocol for Oral Solid Dosage Forms

Purpose and Scope

The purpose of this protocol is to establish a scientifically justified and regulatory-compliant cleaning validation approach specific to the oscillating granulator used in the manufacture of oral solid dosage forms (OSDs). This validation ensures that the cleaning procedures consistently reduce product residues, cleaning agents, and microbial bioburden on product-contact surfaces to levels that prevent contamination or cross-contamination of subsequent batches.

This protocol applies to all oscillating granulators installed in the pharmaceutical production facility and used for granulating APIs and excipients before tablet compression or capsule filling. The scope covers validation of cleaning processes related to equipment disassembly, cleaning execution, sampling, and analytical acceptance criteria for residues and microbial limits where applicable.

The protocol supports compliance with cGMP and regulatory expectations from authorities such as the FDA, EMA, and ICH guidelines related to cleaning validation and cross-contamination control.

Definitions and Abbreviations

Responsibilities

Safety and Personal Protective Equipment (PPE)

All cleaning activities must be carried out in compliance with established safety protocols to protect personnel and maintain product integrity. The following PPE is mandated during cleaning of the oscillating granulator:

1. Protective gloves resistant to detergents and solvents used.
2. Safety goggles or face shield to prevent splashes to the eyes.
3. Protective gown or coverall to prevent contamination of personal clothing.
4. Closed-toe, slip-resistant footwear.
5. Respiratory protection if volatile cleaning chemicals or aerosols are used.

Personnel must be trained on hazards associated with cleaning chemicals (e.g., corrosiveness, flammability) and emergency procedures including eye wash stations and spill response.

Equipment Overview and Product-Contact Parts

The oscillating granulator consists of a stainless steel housing enclosing a perforated screen and oscillating blades driven by a motorized shaft. Product is fed into the granulator hopper, where granules pass through the oscillating blades which reduce particle sizes to the desired distribution for further processing.

The entire product-contact zone can be disassembled to facilitate thorough cleaning and inspection. Parts exposed to product residues must be cleaned to meet acceptance criteria.

Cleaning Strategy Overview

The cleaning strategy adopted for the oscillating granulator is a validated multistep process designed to: remove visible residues, dissolve remaining formulation components, and eliminate detergent residues to levels below allowable safety thresholds. The overall approach includes:

1. Disassembly: Equipment parts in contact with product are disassembled per SOP to ensure cleaning access and avoid hidden residue deposits.
2. Pre-rinse: Initial rinse with warm purified water to remove gross residues.
3. Detergent washing: Soaking and manual cleaning with an approved detergent ([detergent_name]) suited for granulator residues, using brushes and cloths compatible with stainless steel surfaces.
4. Rinse: Multiple rinses with purified water to remove detergent and dissolved residues.
5. Visual inspection: Confirm absence of visible residues or discoloration.
6. Drying: Equipment dried under controlled conditions to prevent microbial proliferation.

The cleaning process accounts for hold times and the impact of delayed cleaning, as well as equipment design features affecting cleanability. The process is documented and periodically reviewed to maintain robustness as operational conditions evolve.

Cleaning Agents and Tools List

Hold Time Definitions

Records and Forms List

Site-specific Inputs Required

• Name and concentration of the detergent used ([detergent_name], concentration %)
• Volumes of water used for rinses ([rinse_volume_L])
• Surface areas of sampling locations on each part ([swab_area_cm2])
• Maximum allowable dirty and clean hold times ([dirty_hold_hours], [clean_hold_hours])
• Cleaning brushes and cloth specifications
• Drying conditions (temperature, duration, method)
• PDE values for APIs and excipients processed on the granulator (for MACO calculation)
• Details of analytical methods employed for residue and detergent detection (TOC, conductivity, HPLC, etc.)
• Microbial risk assessment outcomes for microbial limits inclusion (if applicable)

Oscillating Granulator Cleaning Procedure

1. Pre-Clean Preparation
   1. Ensure the oscillating granulator is fully stopped and isolated from power sources.
   2. Wear appropriate personal protective equipment (PPE) including gloves, gown, and face mask.
   3. Remove any loose granules or product residues with a clean, dry lint-free cloth or vacuum approved for GMP use.
   4. Prepare cleaning materials: [detergent_name] solution at [detergent_concentration], rinse water at [rinse_temperature]°C, clean swabs and sampling containers according to SOP standards.
2. Disassembly
   1. Following the operating manual, carefully dismantle the oscillating granulator components that come into direct contact with product:
      • Granulator screen
      • Rotor assembly
      • Hopper and feed chute
      • Housing covers and seals
   2. Place all dismantled parts on a clean, sanitized surface in a contamination-controlled environment.
   3. Document part identification and location for ease of reassembly.
3. Washing Sequence
   1. Immerse or spray all dismantled components with [detergent_name] solution, ensuring complete coverage of product-contact surfaces.
   2. Agitate or manually scrub components with approved non-abrasive brushes to remove stubborn residues.
   3. Allow the detergent solution to dwell for a minimum of [dwell_time_minutes] minutes to ensure effective cleaning.
   4. For the fixed housing and in-situ surfaces that cannot be dismantled:
      • Apply [detergent_name] solution using a lint-free cloth or cleaning station spray equipment.
      • Scrub using approved brushes or sponges to dislodge product residues.
4. Rinsing Sequence
   1. Rinse all dismantled parts and in-situ surfaces with purified water or WFI (Water for Injection) at [rinse_temperature]°C.
   2. Use [rinse_volume_L] liters of rinse water per component, or until no visible detergent or foam residue remains.
   3. Change rinsing water at defined intervals to avoid recontamination.
   4. Verify visibly clear water run-off during rinsing indicating proper detergent removal.
5. Drying
   1. Dry dismantled parts with clean, lint-free towels or use validated compressed air filtered through a HEPA system.
   2. Ensure all surfaces are dry to avoid microbial proliferation.
   3. For in-situ parts, wipe thoroughly with dry, clean lint-free cloths.
6. Reassembly
   1. Reassemble granulator components as per manufacturer’s instructions.
   2. Verify all fastenings, seals, and fittings are correctly placed and secured.
   3. Document reassembly completion and condition in cleaning log.
7. Visual Inspection
   1. Perform a thorough visual inspection of all product-contact surfaces for residues, discoloration, or damage under controlled lighting conditions.
   2. Use magnifying aids if necessary.
   3. Document findings, including photographs if any residues or anomalies are detected.
   4. If residues are detected, repeat cleaning process prior to sampling.

Process Parameters and Controls

Sampling Plan for Cleaning Validation

Sampling Technique and Handling Instructions

1. Utilize sterile swabs moistened with validated extraction solvent (e.g., [solvent_name]).
2. Swab marked defined surface areas using a standardized S-pattern horizontal strokes followed by vertical strokes ensuring full coverage.
3. Place each swab immediately into pre-labeled, sterile containers to prevent cross-contamination.
4. Maintain chain-of-custody documentation including date/time of sampling, sampler name, equipment ID, batch number, and sample location.
5. Transport samples under controlled temperature conditions (2–8°C unless otherwise specified) to the analytical laboratory within [max_transport_time].
6. Upon receipt, QC personnel log each sample into the Laboratory Information Management System (LIMS) or equivalent documentation system.

Additional Considerations

• Sampling must be performed immediately following visual inspection confirming the absence of visible contamination to ensure residuals are within limits detected only by analytical methods.
• All sampling personnel shall be trained and qualified on cleaning validation sampling techniques.
• Sampling frequency and swab numbers may be adjusted during revalidation or based on risk assessment outcomes.
• Cleaning validation sampling must be coordinated with batch manufacturing schedules to ensure representative contamination scenarios are evaluated.
• Document all sampling deviations, anomalies, or environmental conditions that may affect data integrity.

Site-Specific Inputs Required

• [detergent_name] and associated cleaning detergent concentration (+ validation data)
• [detergent_temperature] for effective detergent application
• [dwell_time_minutes] for detergent interaction time
• [rinse_volume_L] and [rinse_temperature] for effective rinsing
• [swab_area_cm2] standardized swab surface area for sampling
• [max_transport_time] maximum permissible time from sampling to lab analysis
• [solvent_name] validated extraction solvent used for swab sampling

Cleaning Validation Sampling Plan

Sampling Locations

1. Critical contact surfaces of dismantled parts, including granulator screen, rotor assembly, hopper, feed chute, housing covers, and seals.
2. Fixed housing and non-dismantlable surfaces exposed to product residues.
3. Any crevices, joints, and seals prone to residue retention identified during risk assessment.

Sampling Methods

1. Swab Sampling: Use pre-moistened swabs with suitable solvent; swab an area of [swab_area_cm2] cm² per location. Follow SOP for swab preparation and handling.
2. Rinse Sampling: Collect final rinse samples after cleaning to evaluate residual detergent levels using conductivity or TOC analysis.
3. Visual Inspection: Perform under specified lighting to confirm absence of visible residues or soil.

Sample Handling and Documentation

1. Label each sample with unique identification details including equipment ID, sampling location, date, and time.
2. Transport samples to the analytical laboratory under controlled conditions to prevent contamination or degradation.
3. Maintain chain-of-custody documentation and record all deviations and observations during sampling.

Analytical Methodology for Residue Detection

Active Pharmaceutical Ingredient (API) Residue Analysis

1. Use validated analytical techniques such as HPLC, UV-Vis spectrophotometry, or appropriate assays specific to the API.
2. Detection limits and quantitation range must align with cleaning validation sensitivity requirements determined by MACO calculations.
3. Calibration standards and system suitability criteria shall be verified prior to analysis.

Detergent Residue Analysis

1. Apply Total Organic Carbon (TOC) analysis or specific detergent assays validated for [detergent_name] residue quantification.
2. Establish acceptance limits based on method detection limits and toxicological safety thresholds.

Microbial Testing (Risk-Based Application)

1. Conduct microbial limits testing only if risk assessment identifies microbiological contamination potential in oscillating granulator components.
2. Use validated microbial enumeration techniques consistent with USP or equivalent pharmacopeial standards.

Acceptance Criteria

PDE/ADE-Based MACO (Maximum Allowable Carryover) Method

The MACO approach establishes cleaning acceptance criteria by limiting cross-contamination risks through pharmacological thresholds:

1. Calculate MACO using the following formula:
   MACO = (PDE or ADE) × (Batch size of next product) / (Batch size of current product)
2. The PDE (Permissible Daily Exposure) or ADE (Acceptable Daily Exposure) values must be sourced from toxicological assessments or regulatory guidance.
3. Residual API amounts detected via analytical testing must be below the MACO limit for acceptance.

Site-specific inputs required:

• PDE or ADE value for previous product (mg/day)
• Batch size of previous product (kg)
• Batch size of ensuing product (kg)

Detergent Residue Limits

1. Acceptance limits for detergent residues must be based on TOC limits or specific assay thresholds established during method validation.
2. For example, TOC levels should be below [TOC_limit] ppm, or conductivity below [conductivity_limit] µS/cm in rinse samples.
3. Limits should ensure that residual detergents do not pose safety, efficacy, or quality concerns for subsequent batches.

Legacy Acceptance Criteria (Fallback Only)

1. If PDE/ADE data are unavailable, apply legacy limits:
   – API residues must be below 10 ppm on product contact surfaces or 1/1000^th of the therapeutic dose per dose unit.
2. Legacy limits must be explicitly justified as temporary and replaced by MACO-based criteria as soon as data become available.

Documentation and Approval

1. Record all cleaning validation activities including sampling, analysis, and acceptance decision-making in the validation report.
2. Update cleaning SOPs and maintenance schedules based on validation findings.
3. Obtain formal approvals from QA, QC, and Validation departments prior to routine manufacturing use.

Recovery, LOD, and LOQ Expectations

For the oscillating granulator cleaning validation, method sensitivity and accuracy are critical to reliably demonstrate the removal of product and cleaning agent residues. It is expected that swab and rinse sampling analytical methods employed will exhibit:

1. Recovery: Demonstrated recovery must be ≥ 70% from the defined sampling surfaces, validated through spiking studies across multiple concentration levels. This ensures that the method effectively quantifies residual contaminants consistent with site-specific equipment materials and surface finishes.
2. Limit of Detection (LOD): Expected method LOD should be sufficiently low to detect residues well below the Maximum Allowable Carryover (MACO) levels, typically in the low microgram range for active pharmaceutical ingredients (APIs) and detergents.
3. Limit of Quantitation (LOQ): LOQ must be below the established acceptance criteria for residues, providing accurate quantification and reporting, with typical LOQ values at 2 to 5 times the LOD.

Site-specific LOD, LOQ, and recovery validation data must be generated during method validation phases and documented in the Cleaning Validation Master File.

Acceptance Criteria Methodology

PDE/ADE-based MACO Approach

The acceptance criteria for oscillating granulator cleaning validation are established using a scientifically justified PDE (Permitted Daily Exposure) or ADE (Acceptable Daily Exposure) approach, following ICH Q3D and FDA guidelines. This ensures patient safety by limiting cross-contamination risks between sequential batches.

The MACO (Maximum Allowable Carryover) is calculated using the following general equation:

The MACO value represents the maximum residue amount permitted on the cleaned equipment surfaces before use in manufacturing the subsequent product. Residual levels reported in swab and rinse samples must be ≤ MACO to pass validation.

Legacy Acceptance Criteria (Fallback)

As a fallback, where PDE/ADE data is unavailable, legacy acceptance criteria may be used, defined as:

• API residues no greater than 10 ppm (10 μg/g) of the next product dosage concentration or
• A maximum acceptance limit corresponding to 1/1000 of the minimum therapeutic dose of the next product, whichever is more conservative

Legacy limits are considered less scientifically rigorous and should be phased out in favor of PDE/ADE-based MACO calculations wherever feasible.

Detergent Residue Acceptance and Rationale

Cleaning agents, including the site-specific detergent [detergent_name], must be effectively removed to prevent adverse product quality or patient safety impacts. The acceptance criterion for detergent residues is derived from analytical method capability and toxicological data, supported by method-specific controls.

The following rationale guides detergent residue limits:

1. Detergent Residue Analytical Method: Residual detergent quantification will be performed by validated methods such as Total Organic Carbon (TOC), conductivity, or a detergent-specific chemical assay. The method must have a suitably low LOD and LOQ, typically documented as:
• TOC: ≤ [LOD_value] mg C/L
• Conductivity: ≤ [LOD_value] μS/cm (microSiemens per cm)
• Chemical Assay: specific to detergent component, with LOQ ≤ [LOQ_value]
2. Acceptance Criterion: Detergent residues must be below limits established through toxicological review or below detection limits in the validated methods. Often, TOC limits correspond to 10 ppm of detergent residue per total swab area or rinse volume threshold, for conservative safety margins.
3. Justification: Detergents can cause interference with analytical assays, product instability, or patient sensitization. Ensuring removal to validated limits preserves both drug product purity and patient safety.

Site-specific detergent acceptance limits must take into account the detergent chemical composition, surface interactions with oscillating granulator materials, and validated method sensitivity.

Deviations and Corrective and Preventive Actions (CAPA)

Controlled handling of deviations during cleaning validation execution is essential to maintain process integrity. Examples of typical deviations and CAPA include:

All deviations must be captured in the site’s quality management system and reviewed by QA and Validation teams for closure and risk assessment.

Continued Verification Plan

The oscillating granulator cleaning validation requires a structured ongoing cleaning verification program to assure consistent cleaning effectiveness over equipment lifecycle and batch changes. The continued verification plan will typically include:

• Periodic Cleaning Verification: Scheduled re-assessment of cleaning validation per defined frequencies (e.g., annually or after [number_of_batches] batches), utilizing swab/rinse sampling and analytical testing per the validated methods.
• Routine In-Process Monitoring: Visual cleanliness inspections and equipment maintenance records to detect potential cleaning issues early.
• Trending of Cleaning Data: Statistical evaluation of residue levels from routine sampling and cleaning validation runs to identify any upward trends indicating potential process degradation.
• Change Impact Assessment: Review and revalidation driven by process or equipment changes including cleaning agent changes, new products introduced, or new contamination risks identified.
• Operator Training and Competency Assessment: Regular refresher training on cleaning procedures to ensure ongoing compliance.

Revalidation Triggers

Revalidation of the oscillating granulator cleaning procedure and acceptance criteria is warranted upon occurrence of any of the following triggers:

• Change in product formulation or introduction of new product with different toxicological profiles.
• Modification to cleaning agents, detergents, or cleaning procedures that could impact residue removal efficiency.
• Equipment design changes or replacement of major components affecting cleanability.
• Repeated failures to meet acceptance criteria during routine cleaning verification.
• Deviations or CAPA events related to cleaning analyzed and deemed to warrant revalidation.
• Regulatory inspection observations recommending revalidation.

Revalidation scope must be commensurate with the nature and extent of changes or deviations prompting the activity, with documentation maintained under the Validation Master Plan.

Annexures and Templates

The following annexures and templates are appended to support implementation and regulatory compliance of the oscillating granulator cleaning validation program:

1. Annex A: Cleaning Validation Master Plan Template including validation strategy and acceptance criteria overview.
2. Annex B: Sampling Plan Template detailing swabbing locations, rinse volumes, sampling timings, and sample handling procedures.
3. Annex C: Analytical Method Validation Protocol Template specific to swab and rinse residue detection (API and detergent).
4. Annex D: Calculation Worksheet for MACO including PDE/ADE data input, batch sizes, and swab surface factors.
5. Annex E: Deviation and CAPA Report Template for recording and tracking cleaning validation anomalies.
6. Annex F: Cleaning Procedure Verification Checklist for continued verification execution and documentation.
7. Annex G: Revalidation Impact Assessment Form to evaluate and document triggers and scope.

Conclusion

The oscillating granulator cleaning validation acceptance criteria based on a scientifically robust PDE/ADE-derived MACO approach ensure patient safety and regulatory compliance while accommodating site-specific operational characteristics and toxicological risk. Method validation parameters including recovery, LOD, and LOQ establish the analytical reliability needed for confident residue quantification. Detergent residue acceptance limits are grounded in method capability and toxicity considerations to preserve product quality integrity.

A rigorous quality governance framework incorporating deviation management, a structured continued verification program, and clear revalidation triggers collectively support sustained cleaning efficacy over equipment lifecycle and product portfolio changes. The accompanying annexures and templates facilitate systematic protocol implementation and documentation.

By adhering to this cleaning validation framework, pharmaceutical manufacturing sites will achieve validated, compliant cleaning processes for oscillating granulators that protect patient health and meet regulatory expectations for oral solid dosage form production.