Cleaning Validation Protocols

1.0 Objective:

The objective of this protocol is to provide the guideline for the cleaning validation of Lab. glassware.

2.0 Scope:

This procedure is applicable to cleaning of laboratory glassware, which is used for the preparation of test/standard solution and analysis of product/material in the quality control laboratory.

3.0 Requirements:

• Glassware’s used for study.
• Drying oven
• Super clean detergent solution
• UV cabinet
• UV Spectrophotometer
• Nitric acid
• Sodium carbonate
• Acetone
• Riboflavin dye

4.0 Glassware cleaning procedure

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1.0 OVERVIEW

The Dirty equipment hold time is the conditions of storage of used equipment before cleaning commonly referred to as the Dirty Equipment Hold Time (DEHT).

DEHT study shall be performed for a product or a group of products for minimum three run. The DEHT for a representative product for a product group shall be applied to all products in that group as the maximum DHT for routine manufacture.

2.0 PURPOSE

The purpose is to establish the effectiveness of cleaning (Dirty Equipment Hold Time); equipment shall be kept hold in idle condition after manufacturing of product, for example, for 72 hours in dirty condition. After 72 hours, Type – B cleaning (wet Cleaning) shall be performed as per respective equipment cleaning SOP and sampling shall be carried out:

3.0 SCOPE

This Drity equipment hold time protocol is applicable to the Solid oral dosages form, manufactured and packed at the Site.

6.0 DIRTY EQUIPMENT HOLD TIME STUDY APPROACH

The Dirty Equipment Hold Time study shall be executed through an approved protocol and after completion of the study, summary report shall be prepared.

To establish the effectiveness of cleaning (Dirty Equipment Hold Time), equipment shall be kept hold in idle condition, for example, for 72 hours in dirty condition. After 72 hours, Type – B cleaning (Wet Cleaning) shall be performed as per respective equipment cleaning SOP and sampling shall be carried out.

After completion of the study, cleaning of equipment/ equipments shall be done immediately and, the cleaned equipment shall be visually inspected before performing the swab sample for the cleanliness (Cleaned Equipment Hold Time Study). If the equipment found visually cleaned then swab sample shall be collected and sent to the quality control laboratory for the analysis along with the sampling request.

7.0 PRE- REQUISITES  FOR DIRTY EQUIPMENT HOLD TIME STUDY

Following are the pre-requisites for cleaning validation:

• Swab sampling shall be done from all the pre-decided locations as per the current version of SOP.
• The critical parts of equipment, which are difficult to clean, shall be considered for sampling.
• Swab samples shall be analyzed as per laid down test procedures and comply with respect to the predetermined specifications.
• Sterile swab for collection of swab sample should be available before sampling.
• The cleaning shall be done by following the SOP for cleaning of equipment.

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1.0 OVERVIEW

The Cleaned equipment hold time is the time between cleaning and equipment reuse, prior to additional cleaning commonly referred to as the Clean Equipment Hold Time (CEHT).

CEHT study shall be performed for a product/Equipment or a group of products/Equipment for minimum three run. One-time CEHT study shall be performed in equipment train, if more than one equipment trains at the facility, the one which having the complex design of the equipment (which are potential to retain moisture) and / or having hard to clean locations shall be selected for CEHT. The Cleaned equipment hold time study can be executed after completion of Dirty equipment hold time study and after cleaning same equipment/Equipment Train can be considered for the study

2.0 PURPOSE

The purpose is to establish the to establish the expiry of cleaning, equipment shall be kept idle condition after cleaning. Swab / Rinse shall be taken and analyzed for microbiological load level and previous product residue test as per the protocol:

3.0 SCOPE

This Cleaned equipment hold time protocol is applicable to equipment used for the Solid oral dosages form, manufactured and packed at Site.

7.0 CLEANED EQUIPMENT HOLD TIME STUDY APPROACH

The Cleaned Equipment Hold Time study shall be executed through an approved protocol and after completion of the study, summary report shall be prepared.

After Cleaning, the cleaned equipment shall be visually inspected before performing the swab sample for the cleanliness. If the equipment found visually cleaned then swab sample shall be collected and sent to the quality control laboratory for the analysis along with the sampling request.

To establish the effectiveness of cleaning and Storage procedure of Cleaned Equipment (Cleaned Equipment Hold Time), equipment shall be kept hold in idle condition, for example, for 07days in Cleaned condition. After completion of 07 days study, Type – B cleaning (Wet Cleaning) shall be performed as per respective equipment cleaning SOP.

8.0 PRE- REQUISITES  FOR CLEANED EQUIPMENT HOLD TIME STUDY

Following are the pre-requisites for cleaning validation:

• Swab sampling shall be done from all the pre-decided locations as per the current version of SOP.
• The critical parts of equipment, which are difficult to clean, shall be considered for sampling.
• Swab samples shall be analyzed as per laid down test procedures and comply with respect to the predetermined specifications.
• Sterile swab for collection of swab sample for microbiology analysis should be available before sampling.
• The cleaning shall be done by following the SOP for cleaning of equipment.

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1.0 PURPOSE

The objective of this protocol is to collect the sufficient data for establishing the adequacy and reproducibility of equipment cleaning procedure after conducting the Process Simulation Study.

2.0 SCOPE

This protocol is prepared to validate the cleaning procedure of critical contacting process manufacturing equipment used for the Process Simulation Study in Production Block.

5.0 TRAINING

The validation team member shall be trained on the protocol execution of activity and report compilation. The training record shall be attached.

6.0 EXPERIMENTAL PLAN

Samples shall be collected by swab sampling after cleaning of equipment as mentioned under swab sampling technique from the contact part specified.  Simultaneously collect 100 ml of rinse samples from contact parts.

The samples shall be analyzed for the content of residual active ingredient as per validated procedure to establish that the residual level, after cleaning is below the set acceptance criteria.

As per the results, if the parts are found to meet the acceptance criteria, rinse the parts with WFI and sterilize the parts as per the respective

Standard Operating Procedure. If the results do not meet the acceptance criteria, repeat the cleaning procedure on parts and again swab the samples as specified location till it meet the acceptance criteria.

7.0 PRE- REQUISITES FOR AFTER PROCESS SIMULATION STUDY CLEANING VALIDATION

Following are the pre-requisites for cleaning validation:

• Selection of testing plan
• Selection of sampling points
• Determination of acceptance criteria

8.0 CLEANING VALIDATION STUDY OF EQUIPMENT

Manufacturing facility Production block is used for the Process Simulation Study.  Following type and number of equipment are identified for cleaning validation

8.1 Sampling points are selected based on the following criteria:

• Hard to clean area  
• Inaccessible area

8.2 Criteria to be considered for the cleaning validation study

• Contact parts from where the cleaning samples to be withdrawn
• Hard to clean area to have the sampling location as worst-case location
• Hard to access area where from rinse samples is to be collected.
• Total equipment surface area to calculate the maximum allowable carry over per swab.

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1.0 Overview

The Cleaning validation of Worst-Case Product is carrying out in order to provide the high degree of assurance that the equipment cleaning procedure and personal involved in the cleaning process of equipment’s are effective and consistently, repeatedly clean the equipment surface.

2.0 Purpose

The purpose is to provide an outline for the cleaning procedure of equipment to verify that:

• Cleaning procedures are able to clean the equipment’s as mentioned in SOP.
• Cleaning agent used for cleaning of equipment is able to clean the equipment’s.
• Personal verification in involved in the cleaning of the equipment’s.
• Document verification of cleaning procedure.

3.0 Background

The cleaning validation of cleaning procedure is to be carried out on identified worst case product. The worst case identified in cleaning validation master plan shall be validated with three consecutive batch of the product containing Identified worst case.

4.0 Scope

This cleaning validation protocol is applicable to the Tablets dosages form, manufactured at site.

If any new equipment/product introduced then based on the assessment as per the guideline provided in cleaning validation master plan, the cleaning procedure shall be evaluated

5.0 Pre- requisites for Cleaning Validation study

Following are the pre-requisites for cleaning validation:

• The cleaning shall be done by following the SOP for cleaning of equipment.
• Swab/Rinse sampling shall be done from all the pre-defined locations as per the location mentioned in CVMP annexure.
• The equipment’s used for manufacturing shall be as per list of equipment’s.
• The critical parts of equipment, which are difficult to clean, shall be considered for sampling.
• Critical in-process control shall be evaluated with respect to the laid down specification.
• Swab/ Rinse samples shall be analyzed as per laid down test procedures and comply with respect to the predetermined specifications.
• Sterile swab and sterile bottle for collection of swab and rinse sample should be available before sampling

6.0 Swab Sampling Technique

6.1 Hi-Media swab stick or equivalent should be used for swabbing of equipment surfaces for chemical and microbiological analysis.

6.2 Collect the swab sample from hard to clean location as mentioned in the CVMP Annexure

6.3 Swab sample for microbiological analysis shall be collected prior to swab sample for chemical analysis and swab sample should be adjacent to microbial swab.

6.4 For Microbiological analysis swab stick should be sterile prior to use and dipped in 0.9 % sterile saline solution.   

6.5 The surface area should be swabbed is 25 cm². If the surface area less then the 25 cm² complete surface area should be swabbed.

6.6 Swab sample should be taken after the final cleaning cycle from hard to clean location of equipment.

6.7 In case of swab sampling of pipes, do the swabbing in circular motion from outer edge to inner surface in clockwise direction and return the swabbing in similar procedure i.e. from inside to outside in anticlockwise direction.

6.8 In case of swab sampling from groove, do the swabbing in grooves by placing swab stick in grooves and take a stroke in the direction of grooves from both face of grooves to cover the 5 x 5 cm² area

6.9 Wherever dismantling of such equipment/components is possible, dismantle and wash the same with cleaning agent.

6.10 Stainless steel/Teflon/PVC template should be used for determining the surface area of the swab.

6.11 Swab the designated area 5 x 5 cm², using parallel overlapping stroke with slow rotation of swab as mentioned in below diagram

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1.0 Objective

The primary aim of this protocol is to delineate the methodology for qualifying operators engaged in post-manufacturing cleaning procedures for pharmaceutical products. This endeavor is undertaken to guarantee the robustness of the cleaning processes involved. Achievement of this objective will be facilitated through the meticulous establishment of comprehensive documentation for each operator, entailing a rigorous assessment of their adherence to approved cleaning procedures. Furthermore, equipment cleanliness shall be certified subsequent to the attainment of satisfactory outcomes from chemical analysis of swab samples. The criteria for acceptance of these samples shall be defined by the maximum allowable quantity of product residue that maintains the integrity and safety of subsequent products to be manufactured on the equipment.

2.0 Scope

This protocol is applicable to operator performance qualification for cleaning of the equipment used for manufacturing of products at Site.

The scope of this protocol shall be limited to qualify the operators, who perform the cleaning of the equipment.

6.0 Qualification Approach

• Facility Overview:

The facility operates as a multiproduct facility, accommodating multiple products across various batch sizes on shared equipment. Notably, the cleaning procedures are tailored to specific equipment rather than individual products.

• Product Matrix Preparation:

A comprehensive product matrix is devised to guide the cleaning validation process. This matrix assists in identifying the most challenging product scenario(s) for validation purposes. Criteria for selecting the worst-case product(s) include considerations such as product cleanability, Permitted Daily Exposure (PDE) value, and the solubility of Active Pharmaceutical Ingredients (APIs).

• Operator Qualification Criteria:

Operator qualification procedures are aligned with the identified worst-case product, as determined by Approach – I. In instances where the product designated by Approach – I is unavailable, subsequent approaches (Approach – II or Approach – III) or the second worst-case product will be selected for operator qualification.

• Qualification Procedure:

Operator qualification entails successful cleaning of a minimum of three pieces of equipment, adhering to the respective equipment cleaning Standard Operating Procedures (SOPs). This process is followed by visual inspection conducted by production personnel and verification overseen by a Quality Assurance Supervisor.

• Certification of Equipment Cleaning:

The efficacy of equipment cleaning is certified through the attainment of satisfactory analytical results from swab samples collected post-cleaning. These samples are subjected to chemical and microbial analysis to ensure compliance with established standards and guidelines.

• There are following three types of cleaning methods utilized in the drug product manufacturing facility:

  • Clean-In-Place (CIP):

    • Cleaning of the large equipment is performed in place without disassembling and transferring to the Washing area.

    • Cleaning process may be controlled manually or by an automated program.

    • Examples: CIP is applicable for Tablet Auto coaters where Cleaning is performed

  • Clean-Out-Of-Place (COP):

    • Cleaning of disassembled equipment is performed in a common washing area.

    • The automated system also requires validation such as the temperature, ultrasonic activity, cycle time, cleaning operation sequence, water quantity, and detergent quantity dispensed etc. (If applicable)

    • Examples: COP is applicable for Compression Machines and Machines of Bulk Primary Packing, where parts are dismantled and are carried to a washing area for cleaning.

  • Manual Cleaning:

    • Difficult to Clean.

    • Most extensive and elaborate cleaning procedures are required.

    • A high quality and extensive training program is required.

    • Example: Manual Cleaning is Applicable for Manufacturing Process Equipment.

• For all the process Equipments, three types of Cleanings are performed. These are Type A Cleaning, Type B Cleaning and Type C Cleaning.

  • Type A or “Batch to Batch Cleaning”:

    • ‘Type A’ cleaning is performed between two batches of same product.

  • Type B or “Product to Product Cleaning”:

    • ‘Type B’ cleaning is performed between two different products.

  • Type C Cleaning

    • After 7 days of Type B cleaning (Incase equipment is not used within 7 days).

• Identification of Cleaning Method and Type for Execution of Study:

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1.0 Objective

The objective of this Protocol is to establish a standardized framework for evaluating and certifying personnel responsible for conducting swab sampling activities in a pharmaceutical manufacturing facility. This protocol aims to ensure the proficiency and competency of individuals engaged in Swab Sampling for cleaning Validation/Verification or routine swab sampling after equipment cleaning, thereby enhancing the reliability and effectiveness of the cleaning validation process.

The key objectives include meticulously documenting the qualifications of each person involved in swab sampling, rigorously assessing adherence to approved procedures, and certifying based on satisfactory outcomes from chemical analysis of swab samples. Acceptance criteria for these samples will be defined by the maximum allowable quantity of product residue to maintain the integrity and safety of subsequent products manufactured using the equipment

2.0 Scope

This protocol is tailored to oversee the Swab Sampler qualification, the personnel engaged in swab sampling activities within the pharmaceutical manufacturing facility. It encompasses the evaluation and certification of individuals responsible for conducting swab sampling tasks, specifically for cleaning validation/verification procedures or routine sampling post-equipment cleaning after satisfactory visual inspection.

6.0 Qalification Approach

• Facility Overview:

The facility operates as a multiproduct facility, accommodating multiple products across various batch sizes on shared equipment. Notably, the cleaning procedures are tailored to specific equipment rather than individual products.

• Product Matrix Preparation:

A comprehensive product matrix is devised to guide the cleaning validation process. This matrix assists in identifying the most challenging product scenario(s) for validation purposes. Criteria for selecting the worst-case product(s) include considerations such as product cleanability, Permitted Daily Exposure (PDE) value, and the solubility of Active Pharmaceutical Ingredients (APIs).

• Swab Sampling Qualification Criteria:

Swab Sampling qualification procedures are aligned with the identified worst-case product, as determined by Approach – I. In instances where the product designated by Approach – I is unavailable, subsequent approaches (Approach – II or Approach – III) or the second worst-case product will be selected for qualification.

• Qualification Procedure:

Swab Sampling qualification entails successful swab sample from 3 different equipment Worst case locations. The visual inspection of equipment surfaces to be conducted by production personnel and verification overseen by a Quality Assurance Supervisor prior to swab sampling.

• Certification of Swab Sampling Personnel Certification:

The efficacy of swab sampling is certified through the attainment of satisfactory analytical results from swab samples collected post-cleaning. These samples are subjected to chemical and microbial analysis to ensure compliance with established standards and guidelines.

7.0 Swab Sampling Technique

• Hi-Media swab stick or equivalent should be used for swabbing of equipment surfaces for chemical and microbiological analysis.
• Collect the swab sample from the product contact Equipment Surface/Hard to clean location as per SOP.
• For Microbiological analysis swab stick should be sterile prior to use and dipped in 0.9 % sterile saline solution.   
• The surface area should be swabbed is 25 cm2. If the surface area less than the 25 cm2 complete surface area should be swabbed.
• In case of swab sampling of pipes, do the swabbing in circular motion from outer edge to inner surface in clockwise direction and return the swabbing in similar procedure i.e. from inside to outside in anticlockwise direction.
• In case of swab sampling from groove, do the swabbing in grooves by placing swab stick in grooves and take a stroke in the direction of grooves from both face of grooves to cover the 5 x 5 cm2 area.
• Stainless steel/Teflon/PVC template should be used for determining the surface area of the swab.
•  Swab the designated area 5 x 5 cm2, using parallel overlapping stroke with slow rotation of swab as mentioned in below diagram

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