1. Cleaning Validation Master Plan
2. Cleaning Validation Master Plan 2024
3. Cleaning Validation SOP
4. SOP for Cleaning Validation
5. Annexure I
6. Annexure II
7. SOP for Analytical Method Validation
8. Clean Equipment Hold Time Study
9. Dirty Equipment Hold Time Study
10. Analytical Method Validation for Cleaning Validation
11. SOP for Preparation of Cleaning Validation and Hold time shelf life study Protocol & reports
12. Cleaning Validation for Oral Liquid (Mefenamic Acid)
13. Annexure I
14. Annexure II
15. Permitted Daily Exposure (PDE) in Cleaning Validation
16. Decontamination of steroid residue from the Ointment Facility
17. Sketches of Equipment
18. Calculation for Equipment Surface area
19. Analytical Method Validation Protocol for Pre & Probiotic Capsules
20. Analytical Method Validation Report for Pre & Probiotic Capsules
21. SOP for Cleaning Validation of Swab Sample
22. Protocol cum Report for Visual Detection Limit
23. Cleaning Validation Protocol for Cepha Section
24. SOP for Cleaning Validation 1
25. Flow chart for evaluation of new product introduction at site
26. Annexure II Active Ingredient Name in Drug Product
27. Cleaned Equipment Hold time study protocol
28. Dirty Equipment Hold Time Study Protocol Cum Report
29. Dirty Equipment Hold Time Study Protocol Cum Report for Oral Liquid
30. Cleaning Validation Protocol
31. SOP for Cleaning Validation
32. DEHT protocol blank
33. Cleaning Validation Master Plan
34. Annexure I Cleaning Validation flow chart
35. Annexure-II Surface Area Calculation
36. Annexure-III Rating Criteria
37. Annexure-IV Summary of Toxicological Assessment and HBEL PDE Value of API molecules handled at site
38. Annexure VI Decision for Cleaning Validation
39. Annexure VII Dose administration as per MHRA Site
40. Product Matrix
41. Equipment matrix
42. Appendix-I for CVMP
43. SOP for Cleaning Validation
44. Annexure I Cleaning Validation flow chart
45. Annexure II Active Ingredient Name in Drug Product
46. Cleaning Validation Protocol for Glimepiride Tablets
47. Cleaning Validation Report for Glimepiride tablets
48. Annexure-I Equipment Detail & Cleaning Procedure
49. Annexure-II Calculation for traces of Glimepiride in rinse
50. Annexure-III Calculation & Acceptance for traces of Methanol in rinse
51. Annexure-IV Cleaning Details
52. Annexure-V Swab Sampling location for Microbiology
53. Annexure-VI Swab Sampling details Microbiology
54. Annexure-VII Result Recording for Microbiology
55. Annexure-VIII Swab Sampling location for Chemical
56. Annexure-IX Swab Sampling details Chemical
57. Annexure-X Result Recording for Chemical
58. Annexure-XI Sampling details Methanol Rinse
59. Annexure-XII Rinse result record for Methanol
60. Annexure-XIII Cleaning Details after Methanol Rinse
61. Annexure-XIV Sampling details after Purified Water
62. Annexure-XV Rinse result record for Methanol Traces
63. Cleaning Validation of Lyophilizer
64. Protocol for Cleaning Validation – Production Lyophilization
65. Protocol for Determination of Visual Residue Limit
66. Installation Qualification for eResidue Application
67. OperationaI Qualification for eResidue Application
68. Performance Qualification for eResidue Application Version 2.0.0
69. SOP for Operation of eResidue Software 2.0.0
70. Summary of eRESIDUE Application 2.0.0
71. Protocol for Dirty Equipment Hold Time
72. Protocol for Clean Equipment Hold Time Study Validation (Oncology)
73. Cleaning Validation Protocol (Production Formulation)
74. Cleaning Validation Protocol for Active Pharmaceutical Ingredients
75. Cleaning Validation Protocol for Blending
76. Record of Observations for eResidue Application Version 2.0.0
77. List of Masters and Observers Required for Inspection of Visual Residue
78. Recording the Visual Inspection Observation on Different Coupons
79. Cleaning Validation Protocol-Levonorgestrel Tablets 1.5 mg
80. Annexure-1 Summary Sheet
81. Annexure-1 Training Record
82. Annexure-2 Equipment Details
83. Annexure-3 Product Details
84. Annexure-4 Equipment Grouping
85. Annexure-5 Calculation of Contamination Limit
86. Annexure-6 Swab Sampling Locations of Equipments
87. Annexure-7 Visual Inspection Results
88. Annexure-8 Chemical & Instrumental Analytical Results
89. Annexure-9 Microbiological Results
90. Annexure-11 List of Deviations
91. Annexure-12 Material Safety Data Sheets
92. SOP for Cleaning Validation (PDE)
93. Cleaning Validation Protocol for Ampoules
94. Cleaning Validation Report for Ampoules
95. Cleaning Validation Protocol for Dry Powder Injection
96. Cleaning Validation Report for Dry Powder Injection
97. Cleaning Validation Protocol for Three Piece
98. Cleaning Validation Report for Three Piece
99. Cleaning Validation Protocol for Liquid Vial
100. Cleaning Validation Report for Liquid Vial
101. SOP for Cleaning Validation (HBEL)
102. Cleaning Validation Protocol for Ampoule Line
103. Cleaning Validation Report for Ampoule Line
104. Annexure-I Equipment Detail & Cleaning Procedure
105. Annexure-II Calculation for traces of Furosemide Injection in Rinse
106. Annexure-III Calculation & Acceptance for traces of Methanol in rinse
107. Annexure-IV Cleaning Details
108. Annexure-V Swab sampling location for Micro
109. Annexure-VI Swab Sampling Details Micro
110. Annexure-VII Result Recording for Micro
111. Annexure-VIII Swab Sampling Location for Chemical
112. Annexure-IX Swab Sampling Details Chemical
113. Annexure-X Result Recording for Chemical
114. Annexure-XI Sampling Details Methanol Rinse
115. Annexure-XII Rinse Result Record for Furosemide Traces
116. Annexure-XIII Cleaning Details after Methanol Rinse
117. Annexure-XIV Sampling details after Purified Water
118. Annexure-XV Rinse Result Record for Methanol Traces
119. Annexure-XVI Instruments Calibration Status
120. Establishment Protocol for Visual Detection Limit of Furosemide
121. Clean Equipment Hold Time Study (Oncology)Liquid Vial
122. Dirty Equipment Hold Time Study (Oncology)Liquid Vial
123. Cleaning Validation Protocol for Serratiopeptidase Tablets
124. Cleaning Validation Report for Serratiopeptidase Tablets
125. Cleaning Validation Protocol for Tablet (Cephalosporin Block)
126. Cleaning Validation Report for Tablet (Cephalosporin Block)
127. Cleaning Validation Report for Vibratory Sifter
128. Cleaning Validation Report for Rapid Mixer Granulator
129. Cleaning Validation Report for Fluid Bed Dryer
130. Cleaning Validation Report for Tray Dryer
131. Cleaning Validation Report for Multi-Mill
132. Cleaning Validation Report for Octagonal Blender
133. Cleaning Validation Report for Tablet Inspection Machine
134. Cleaning Validation Report for Fluid Bed Coater
135. Cleaning Validation Report for Compression Machine
136. Cleaning Validation Report for Coating Pan
137. Cleaning Validation Report for Blister Packing Machine
138. Cleaning Validation Report for Strip Packing Machine
139. Cleaning Validation Protocol for Dry Powder Injection
140. Cleaning Validation Report for Dry Powder Injection

Cleaning Validation in Pharma – Step-by-Step Guide

Cleaning Validation is a documented proof that a cleaning procedure consistently removes residues of previous products, cleaning agents and microorganisms to a pre-defined, acceptable level.

In the pharmaceutical industry, cleaning validation is critical to:

• Prevent cross-contamination
• Ensure patient safety
• Comply with GMP / cGMP and regulatory expectations
• Maintain confidence in multi-product facilities

What Is Cleaning Validation?

Definition:
Cleaning validation is a documented process that demonstrates, with a high degree of assurance, that a cleaning procedure can repeatedly and effectively clean equipment used in the manufacture of pharmaceutical products.

It ensures that after cleaning, the equipment is:

• Visually clean
• Free from unacceptable levels of product residues
• Free from unacceptable levels of cleaning agents
• Free from unacceptable levels of microbial contamination

Objectives of Cleaning Validation

• To ensure that residues do not carry over into the next product at levels that may:
  • Affect safety
  • Alter efficacy
  • Impact quality attributes (assay, impurities, appearance, etc.)
• To establish scientifically justified limits
• To prove that the cleaning procedures are robust, reproducible and controlled
• To support the multi-product use of facilities and equipment

Regulatory Expectations (High Level)

Global regulatory agencies expect that:

• A cleaning validation program is defined, risk-based and documented
• Acceptance criteria are science-based and justified
• Worst-case products and scenarios are identified and validated
• Analytical methods are sensitive, specific and validated for residue detection
• Cleaning processes are part of a continued verification / lifecycle (not a one-time exercise)

Key Concepts & Terminology

• Product Residues – Active ingredient, intermediates, excipients, degradants
• Cleaning Agent Residues – Detergents, solvents, disinfectants
• MACO (Maximum Allowable Carryover) – Maximum amount of residue allowed to carry over to the next product
• Worst-Case Product – Product that is hardest to clean and most potent/toxic
• Swab Sampling – Direct sampling of surfaces with swabs
• Rinse Sampling – Sampling of rinse solution after cleaning
• Recovery Factor – Percentage of residue recovered by the sampling method

Cleaning Validation Lifecycle – Overview

1. Define scope & equipment
2. Perform risk assessment and grouping (products & equipment)
3. Identify worst-case scenarios
4. Set acceptance criteria and calculate limits
5. Develop and optimize cleaning procedures
6. Select & validate analytical methods
7. Define sampling strategy and locations
8. Execute validation runs (typically 3 consecutive successful runs)
9. Evaluate data and prepare validation report
10. Maintain ongoing control (requalification, periodic review)

Step-by-Step: Cleaning Validation in Pharma

Step 1: Define Scope & Equipment

• List all equipment requiring cleaning validation:
  • Mixers, blenders, granulators, tablet presses
  • Tanks, reactors, filters, filling lines, transfer lines, etc.
• Identify product-contact surfaces and materials of construction (SS, glass, PTFE, etc.)
• Identify cleaning processes:
  • CIP (Clean-In-Place)
  • COP (Clean-Out-of-Place)
  • Manual cleaning

Step 2: Product & Equipment Grouping

To make the program manageable:

• Group products based on:
  • Potency (high/low)
  • Toxicity, therapeutic dose
  • Solubility and cleanability
  • Route of administration (oral, parenteral, etc.)
• Group equipment based on:
  • Design and function
  • Size and complexity
  • Similar cleaning procedures

Use bracketing and matrix approaches to minimize the number of validation studies, while still covering worst-case scenarios.

Step 3: Identify Worst-Case Products

Worst-case products are typically those that are:

• Most difficult to clean (poor solubility, sticky, viscous, adherent)
• Most potent or toxic (low therapeutic dose)
• Highest risk route of administration (e.g. parenteral > oral)
• Highest batch size or largest contact surface area

These products are selected as representatives for validation of a product group.

Step 4: Establish Acceptance Criteria (Limits)

Cleaning limits must be scientifically justified and practical.

Common approaches for setting limits:

1. Therapeutic Dose-Based
   • Typically based on a fraction of the minimum daily dose of the previous product carried over into the maximum daily dose of the next product.
2. Toxicity / PDE-Based
   • Based on NOEL, NOAEL, or PDE (Permitted Daily Exposure) of the previous product.
3. 10 ppm Approach (historical)
   • Not more than 10 ppm of previous product in next product – used cautiously and with justification.
4. Cleaning Agent Limits
   • Based on toxicological data or supplier specification (e.g. mg/day).
5. Visual Cleanliness
   • “Visually clean” is required but not sufficient alone. It should be supported by quantitative limits.

Limits are often expressed as:

• µg/cm² of surface area
• µg/mL of rinse sample
• µg per swab

Step 5: Analytical Method Selection & Validation

Analytical methods must be capable of detecting residues at or below the established limits.

• Choose methods such as:
  • HPLC / UPLC
  • UV-Vis spectrophotometry
  • TOC (Total Organic Carbon)
  • Specific assays for cleaning agents (titration, ion chromatography, etc.)
• Validate methods for:
  • Specificity
  • Linearity
  • Accuracy
  • Precision
  • Limit of Detection (LOD)
  • Limit of Quantitation (LOQ)
  • Recovery from surfaces and rinse media

Step 6: Sampling Strategy

Define how and where samples will be collected:

6.1 Swab Sampling

• Used for hard-to-reach areas and flat surfaces.
• Define:
  • Swab type and material
  • Swab area (e.g. 25 cm²)
  • Swabbing technique (pattern, pressure, direction)
  • Extraction procedure for analysis

6.2 Rinse Sampling

• Used when surfaces are inaccessible (pipes, internal vessel surfaces).
• Rinse a defined volume of solvent (usually water) through or over the equipment.
• Analyze the collected rinse for residues.

6.3 Sampling Locations

Identify worst-case locations, such as:

• Dead legs, gaskets, valves, corners
• Impellers, shafts, transfer lines
• Areas known to be difficult to clean

Location selection should be justified and documented (e.g. via risk assessment or previous experience).

Step 7: Number of Validation Runs

Typically:

• Perform three (3) consecutive successful cleaning validation runs for each defined cleaning procedure and worst-case scenario.

Each run should represent routine manufacturing and cleaning conditions:

• Same operators or representative operators
• Same cleaning materials, detergents and tools
• Same contact times, temperatures, and procedures

For campaign production, define and validate the maximum campaign length (number of batches before a full clean is required).

Step 8: Microbiological & Endotoxin Aspects

For products and equipment where bioburden or endotoxin is critical (e.g. sterile or non-sterile liquids):

• Establish limits for microbial counts and, where applicable, endotoxins.
• Validate cleaning and, if applicable, sanitization / disinfection procedures.
• Include microbiological sampling as part of cleaning validation or separate microbial control validation.

Step 9: Hold Time & Dirty Equipment Hold Time Studies

• Dirty Hold Time: Maximum allowable time between end of manufacturing and start of cleaning.
• Clean Hold Time: Maximum allowable time between end of cleaning and start of the next batch.

Studies should demonstrate that residues and microbial growth do not increase beyond acceptable levels within defined hold times.

Step 10: Evaluation & Validation Report

For each cleaning validation study:

• Compile all:
  • Raw data
  • Analytical results
  • Calculations
  • Deviations and investigations
• Summarize in a Cleaning Validation Report including:
  • Objective and scope
  • Equipment and product details
  • Sampling plan and methods
  • Results vs. acceptance criteria
  • Discussion of deviations/OOS results
  • Final conclusion (Pass/Fail)
  • Approval signatures (QA, QC, Manufacturing, Validation)

Ongoing Verification & Revalidation

Cleaning validation is not “once and done.”

Revalidation or review is needed when:

• New product with different potency/toxicity is introduced
• Process or cleaning procedure is changed
• New equipment design is introduced
• Repeated failures, trends or deviations occur
• At defined intervals as per site SOP

Routine monitoring (e.g. periodic swab/rinse tests) supports continued control.

Roles & Responsibilities

• Manufacturing: Follow approved cleaning procedures, document each step, report issues.
• Quality Control (QC): Perform and report analytical testing of samples.
• Validation / Technical / Engineering: Design and execute cleaning validation studies, perform risk assessments.
• Quality Assurance (QA): Approve protocols, monitor execution, review and approve reports.

Sample FAQs for Cleaning Validation

Q1. Why is cleaning validation required in the pharmaceutical industry?
To ensure that no harmful or significant residues of previous products, cleaning agents or microorganisms carry over to subsequent batches, which could compromise patient safety and product quality.

Q2. How many runs are needed for cleaning validation?
Typically, three consecutive successful cleaning runs are required for each cleaning procedure and worst-case scenario, unless otherwise justified by a risk-based scientific approach.

Q3. What is MACO in cleaning validation?
MACO (Maximum Allowable Carryover) is the maximum amount of a residue from a previous product that is allowed to be present in shared equipment without posing any risk to the next product or patient, based on toxicological or therapeutic limits.

Q4. What is the difference between swab and rinse sampling?

• Swab sampling collects residues directly from defined surface areas (e.g. 25 cm²).
• Rinse sampling collects residues from areas not accessible to swabs, by rinsing equipment with a solvent and testing the rinse.
  Often, a combination of both is used.

Q5. When is revalidation of cleaning required?
Revalidation is needed when there are significant changes in product, process, cleaning procedure, equipment, or when recurring failures or trends suggest that the validated state might be compromised.