Cleaning Validation in Pharmaceutical Manufacturing - A Regulatory Perspective - Part 2/3
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This document discusses cleaning validation in pharmaceutical manufacturing from a regulatory perspective. It provides guidance on developing cleaning procedures, validation protocols, sampling methods, analytical methods, and establishing acceptance criteria. It emphasizes that cleaning procedures and validation studies must be thoroughly documented and specific. The validation approach should consider factors like equipment design, products manufactured, and difficulty of cleaning. Deviations and out-of-specification results must be properly investigated. The goal of cleaning validation is to prove cleaning procedures adequately remove residues to predetermined acceptable levels.
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Cleaning Validation in Pharmaceutical Manufacturing - A Regulatory Perspective - Part 2/3
- 1. Cleaning Validation in Pharmaceutical Manufacturing A Regulatory Perspective Part 2/3 How do you know that your clean is clean? Roohi B. Obaid 06 April 2019
- 3. Production Cleaning procedures Laboratory Analytical procedures Data Data Integration
- 9. Appropriate, adequate, suitable and inert
- 10. Appropriate, adequate, suitable and inert Why
- 11. Appropriate, adequate, suitable and inert Why To facilitate operation for its intended use & for its cleaning as well as maintenance
- 14. Surface that contact components, in process materials or drug products are not reactive, additive or absorptive Constructed inert Why
- 15. To prevent contact with substance required for operations such as lubricants and coolants Constructed inert Why
- 16. Cleaning & maintenance activities are to prevent malfunctions which could lead to contamination of a drug product
- 17. Written procedures for cleaning and maintenance of equipment should be established & followed
- 18. Records shall be kept for cleaning, sanitizing, maintenance & inspection
- 19. SOPs should include Responsibility for equipment cleaning & maintenance
- 20. SOPs should include Cleaning & Sanitization Schedules
- 21. SOPs should include Detail description of cleaning
- 22. SOPs should include Removal of previous batch identification
- 23. SOPs should include Protection of clean equipment
- 24. SOPs should include Inspection of equipment prior to use
- 25. Regulatory Expectations Written procedures to prevent objectionable microorganisms in drug product
- 26. Regulatory Expectations Written record of major equipment cleaning & use included in individual equipment logs
- 27. Regulatory Expectations Date, time, product & lot number of each batch processed
- 28. From Regulator’s Eye Documentary evidences that The equipment is consistently cleaned of product, microbial and cleaning agent residues to predetermined, acceptable levels
- 29. Inside File Objective of cleaning process
- 31. Inside File Cleaning procedure (Step by step) Documentation
- 32. Inside File Cleaning agent / Detergent
- 34. Inside File Sampling (location, number, method, tools)
- 38. Inside File Cleaning of chemical residue & microorganisms
- 39. Remember please Test until clean is NOT Cleaning Validation
- 40. Cleaning procedure is the initial starting point
- 41. Analytical method & its limits are the tools that support the effectiveness of cleaning procedure
- 42. Objective of the exercise To prove that cleaning procedure is adequate
- 43. Cleaning validation approach e.g. matrix or product specific, dedicated vs. non-dedicated equipment, campaigns, CIP/disassembly
- 44. Is some equipment more difficult to clean (e.g. mills, fluid bed dryers, piping, rubber gaskets, etc.)?
- 45. Identify types of products manufactured e.g. drug products industrial chemicals
- 46. Were there any OOS results or trends during cleaning validation studies?
- 47. Were there unknown peaks in unrelated laboratory chromatograms?
- 48. Be Alert to auxiliary equipment or containers that may be re-used and/or not included in the cleaning validation
- 49. Identify critical pieces of equipment for evaluation of cleaning validation based on previously gathered information, It includes past difficulty in achieving cleaning status, observed adverse trends, hazard to intended patient population, potency or toxicity of drug product, degradants, excipients etc.
- 50. Cleaning tools Brush, wipes, sponges etc. Must be Specific CP
- 51. Sequence of cleaning steps Must be Specific CP
- 52. Critical steps identified including rationale (in line with protocol) Must be Specific CP
- 53. Instructions for disassembling & assembling of equipment or parts Types of valves, gasket & seal used How residue will be removed Must be Specific CP
- 54. Use of dedicated versus multi product equipment Must be Specific CP
- 55. Cleaning between batches of same or different products Must be Specific CP
- 56. Clean-In-Place (CIP) Identification of piping & valves Valves & pumps should be of sanitary design Must be Specific CP
- 57. Type, amount, concentration & temperature of cleaning agent and how they should be applied Must be Specific CP
- 58. Temperature & Quality of Water Must be Specific CP
- 59. Washing, rinsing or scrubbing methods & times Must be Specific CP
- 60. Instructions • Rinse, if needed • Rinse, if specifications are not met. Then re-sample • Use rag or brush as needed Must be Specific CP
- 61. Drying and storage Must be Specific CP
- 62. Instructions to perform at least a visual inspection after every cleaning Must be Specific CP
- 63. (Dirty Hold Times) Time b/w processing & cleaning • Residue may dry out become more difficult to clean • May also increase microbial burden Must be Specific CP
- 64. Direct surface sampling (Swab) Area hardest to clean can be evaluated Sampling
- 65. Rinse sampling • Greater surface coverage • Inaccessible area can be sampled • Should be direct measurement of residue • Insoluble residues are not tested Sampling
- 66. Recovery studies It should be representative of all major Product contact surfaces For e.g. Stainless steel, teflon, etc. & Sampling methods (rinse or swab)Analytical Method
- 67. Challenge the analytical method in combination with the sampling Specificity Sensitivity Recovery Analytical Method
- 68. Specific assay test methods such as HPLC Analytical Method
- 69. Specific test such as Total Organic Carbon (TOC) Advantage – less analysis time Disadvantage – lack of specificity Can be used if TOC is sensitive to the compounds being cleaned away Analytical Method
- 70. Specific test such as Total Organic Carbon (TOC) Advantage – less analysis time Disadvantage – lack of specificity Can be used if TOC is sensitive to the compounds being cleaned away Analytical Method
- 71. Specific test such as Total Organic Carbon (TOC) Advantage – less analysis time Disadvantage – lack of specificity Can be used if TOC is sensitive to the compounds being cleaned away Analytical Method
- 72. Specific test such as Total Organic Carbon (TOC) Advantage – less analysis time Disadvantage – lack of specificity Can be used if TOC is sensitive to the compounds being cleaned away Analytical Method
- 73. Limit should be based on scientific rationale A good scientific rationale should be logical, practical, verifiable, safe & achievableEstablishment of Limits
- 74. If flexibility of rational offered, please remember A good scientific rationale should be logical, practical, verifiable, safe & achievableFreedom to establish limits GMP Zone
- 75. How clean is clean? There is no clean answer but simple Use water for washing floor, for washing pots, for cooking foods, for drinking, for use of syrup, for injectionLets resolve cleanliness
- 76. Let’s use logic to decide boundary of digit • Therapeutic dosage levels • Toxicity Profile • Solubility of the residue (detergent) • Batch size & nature of other products made in the same equipment Moving upward ..
- 77. Nature of the Dosage Form • Parenteral • Opthalmic • Topicals • Liquids • Solid oral Establishment of Limits
- 78. Who is responsible for doing cleaning validation Who for what … Validation Protocol Inspection Approach
- 79. Who approves it Validation Protocol Inspection Approach
- 80. What is Acceptance Criteria Validation Protocol Inspection Approach
- 81. Specific Sampling Plan Validation Protocol Inspection Approach
- 82. Analytical method qualified for the purpose Validation Protocol Inspection Approach
- 84. Review the CV report Evaluation of CV studies Inspection Approach
- 85. Review cleaning records Evaluation of CV studies Inspection Approach
- 86. Review raw data for swab & for rinse sample Evaluation of CV studies Inspection Approach
- 87. Verify the compliance of Acceptance Criteria (Data Integrity) Evaluation of CV studies Inspection Approach
- 88. Confirm that all deviations & OOS results were adequately investigated Evaluation of CV studies Inspection Approach
- 89. Verify batch to batch consistency Evaluation of CV studies Inspection Approach
- 90. Cleaning procedure too vague Issues & Concerns Significant
- 91. Operator’s performance & reproducibility Training? Issues & Concerns Significant
- 92. Inadequate investigations & corrective actions for unknown peaks in cleaning validation samples Issues & Concerns Significant
- 93. Re-cleaning, re-sampling & retesting of equipment (“test until clean”) without investigating the root cause for the OOS resultsIssues & Concerns Significant
- 94. Failure to evaluate/improve cleaning procedures and/or operator performance Issues & Concerns Significant
- 95. Failure to properly disassemble equipment for cleaning Issues & Concerns Significant
- 96. Failure to specify & validate dirty hold time, or equipment remains dirty for extended periods exceeding those validated Issues & Concerns Significant
- 97. Interview of operators disclosed that cleaning procedures are not always followed Issues & Concerns Significant
- 98. Worst case surfaces e.g. Gaskets, Rubber seals, Difficult to clean spots not always sampledIssues & Concerns Significant
- 99. Use of common equipment to manufacture potent (e.g. steroids) and non potent drugs Without adequate cleaningIssues & Concerns Significant
- 101. Review the Cleaning Validation protocol/report Summary
- 102. Review the raw data for swab and/or rinse samples Summary
- 103. Verify that the cleaning procedures are specific & were followed during the C.V. studies Summary
- 104. Verify that pre-determined acceptance criteria were met Summary
- 105. Confirm that all deviations/OOS results were adequately investigated & corrective actions implemented Summary
- 106. Verify batch to batch consistencySummary
- 109. Training Summary
- 111. Thanks