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Cleaning validation a complete know how

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A complete illustration of Cleaning Validation is Pharmaceutical Dosage forms

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Cleaning validation a complete know how

  1. 1. Know – How of an Effective Cleaning Program Sambhujyoti Das, Quality Assurance CLEANING VALIDATION
  2. 2. CLEANING VALIDATION…………………... AT A GLANCE After completing this session we’ll come to know :  Definition  Purpose  Cleaning mechanisms  Cleaning agents  Cleaning Methods  Cleaning parameters  Cleaning continuum  Grouping strategies  Worst Case considerations 1 Quality Assurance  Acceptance criteria  Sampling Methods  Analytical Methods  Hold time studies  USFDA 483 Citations
  3. 3. CLEANING VALIDATION……………… THE DEFINITION The process of removing contaminants from process equipment and monitoring the condition of equipment such that the equipment can be safely used for subsequent product manufacturing. Dustin A. Leblanc. 2 Quality Assurance
  4. 4. CLEANING VALIDATION…………………........... PURPOSE  Product integrity Cross contamination Microbial integrity Product impurity Batch integrity  Equipment reuse  Regulatory issues 3 Quality Assurance
  5. 5. CLEANING VALIDATION…………CLEANING MECHANISMS The chemistry of contaminant removal :  Solubility  Wetting  Emulsification  Dispersion  Hydrolysis  Oxidation  Physical removal  Antimicrobial action 4 Quality Assurance
  6. 6. CLEANING VALIDATION…………CLEANING MECHANISMS Solubility : Solubility involves the dissolution of one chemical (the contaminant) in a liquid solvent. For example, salts may be soluble in water, and certain organic actives may be soluble in acetone or methanol. One of the primary cleaning mechanisms to be considered during design phase. Rate of solubility, Insoluble form, Soluble – Insoluble species 5 Quality Assurance
  7. 7. CLEANING VALIDATION…………CLEANING MECHANISMS Wetting : Wetting involves the displacement of one fluid from a solid surface by another fluid. Wetting can be improved by the addition of surfactants. It improve penetration of the cleaning solution into cracks and crevices, which are usually difficult-to clean locations. 6Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc Quality Assurance
  8. 8. CLEANING VALIDATION…………CLEANING MECHANISMS Emulsification : Breaking up an insoluble liquid residue into smaller droplets and then suspending those droplets throughout the water. Emulsion = Mechanical energy + Surfactants / Polymers. Emulsions are thermodynamically unstable (say, 5 to 10 mins.). Redeposition of the cleaned residue back onto the equipment surfaces. Agitation should be continued till the time to discharge the cleaning solution to the drain. 7 Quality Assurance
  9. 9. CLEANING VALIDATION…………CLEANING MECHANISMS Dispersion : Dispersion is similar to emulsification, except that it involves the wetting and deaggregation of solid particles and then the subsequent suspension of those particles in water. More important in dry product manufacturing. Hydrolysis : This involves the cleavage of certain bonds in an organic molecule. The resultant hydrolyzed residues must either be water soluble or solubilized at the pH of the cleaning solution. 8 Quality Assurance
  10. 10. CLEANING VALIDATION…………CLEANING MECHANISMS Oxidation : This involves the cleavage of various organic bonds, such as carbon-carbon bonds, by the action of a strong oxidizing agent. Large Non-polar Mol. Smaller more polar Mol. Antimicrobial Action : Mechanisms that may kill organisms but leave behind nonviable microbial residues. Special type of mechanism, sterilization, disinfection. 9 Quality Assurance
  11. 11. CLEANING VALIDATION…………CLEANING MECHANISMS Physical Removal: Cleaning by some mechanical force. the objective is to physically displace the residue. Pressurized water + Scrubbing 10 In real life situation, more than one cleaning mechanisms are being used. Quality Assurance
  12. 12. CLEANING VALIDATION……………….CLEANING AGENTS Cleaning Agents 11 Aqueous Cleaning Organic Solvents Water Surfactants Chelants Solvents (miscible) Acids / Bases Oxidants Quality Assurance
  13. 13. 12 CLEANING VALIDATION……………….CLEANING AGENTS Organic Solvents • Acetone • Methanol • Ethyl Acetate Surfactants • SLS • SDS • Fatty acid salts Chelants • EDTA • NTA • SHMP Solvents (miscible) • Glycol Ethers Bases • NaOH • KOH Acids • Glycolic Acid • H3PO4 • Citric Acid Oxidants • NaOCl • Peracetic Acid • H2O2 Quality Assurance
  14. 14. CLEANING VALIDATION…………….CLEANING METHODS Automated Cleaning: o Fixed CIP o Portable CIP o Parts Washer o Ultrasonic 13 Manual Cleaning: Soak Brush Wipe Spray Extent of automation……………..Extent of disassembly Quality Assurance
  15. 15. CLEANING VALIDATION…………….CLEANING METHODS Fixed CIP : 14 Quality Assurance
  16. 16. CLEANING VALIDATION…………….CLEANING METHODS Portable CIP : 15 Quality Assurance
  17. 17. CLEANING VALIDATION…………….CLEANING METHODS Parts Washer : 16 Ultrasonic Washer : Quality Assurance
  18. 18. CLEANING VALIDATION…….……CLEANING PARAMETERS  Time  Action  Cleaning chemistry  Concentration  Temperature  Mixing / flow / turbulence  Water quality  Rinsing 17 Quality Assurance
  19. 19. Parameter interactions : 18 CLEANING VALIDATION…….……CLEANING PARAMETERS Time vs Concentration : Temp. vs Concentration : Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc Quality Assurance
  20. 20. Parameter interactions : 19 CLEANING VALIDATION…….……CLEANING PARAMETERS Time vs Temperature : Time (min) Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc Quality Assurance
  21. 21. CLEANING VALIDATION…….……CLEANING CONTINUUM 20 Continuum represent the extremes in the range of operating differences found within the industry. The continuum should be used during the initial phases of defining a cleaning validation program or during new product development. Manual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Automated Cleaning COP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..CIP Dedicated Equipment . . . . . . . . . . . . . Non-Dedicated Equipment Product Contact Surfaces . . . . . . . Non-Product Contact Surfaces Non-Critical Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Critical Site Minor Equipment . . . . . . . . . . . . . . . . . . . . . . . . Major Equipment Quality Assurance
  22. 22. CLEANING VALIDATION…….……CLEANING CONTINUUM 21 Low Risk Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . High Risk Drugs Highly Characterized . . . . . . . . . . . . . . . . . . . Poorly Characterized Sterile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Sterile Solid Formulations . . . . . . . . . . . . . . . . . . . . . Liquid Formulations Soluble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insoluble Single Product Facility . . . . . . . . . . . . . . . Multiple Product Facility Campaigned Production . . . . . . . . . Non-Campaigned Production Simple Equipment Train . . . . . . . . . . . Complex Equipment Train Quality Assurance
  23. 23. CLEANING VALIDATION…….……GROUPING STRATEGIES 22 "Grouping" is the concept of demonstrating that certain elements of cleaning are of a similar type, and selecting one (or more) representative object(s) on which to conduct the Cleaning Validation (Cleaning Process Qualification). Product grouping :  Same manufacturing equipments being used.  Same cleaning SOPs being followed.  Similar formulations.  Similar risk / therapeutic group. Equipment grouping, Cleaning method grouping, Cleaning agent grouping, …………….., etc. Quality Assurance
  24. 24. CLEANING VALIDATION…….……GROUPING STRATEGIES 23 Sr. No. Name of product Formulation Cleaning methods Equipment train Risk / Therap. class 1 Product A Tablet (FC) Method 1 Train A General 2 Product B Tablet Method 1 Train B General 3 Product C Parenteral Method 2 Train C Cytotoxic 4 Product D Tablet Method 3 Train B General 5 Product E Tablet (EC) Method 4 Train A General 6 Product F Parenteral Method 2 Train C Cytotoxic 7 Product G Tablet (FC) Method 1 Train A Cytotoxic 8 Product H Tablet Method 3 Train B General 9 Product I Tablet (EC) Method 4 Train A General 10 Product J Parenteral Method 2 Train C Cytotoxic All products in a facility (hypothetical): Quality Assurance
  25. 25. CLEANING VALIDATION…….……GROUPING STRATEGIES 24 Sr. No. Name of product Formulation Cleaning methods Equipment train Risk / Therap. class 1 Product A Tablet (FC) Method 1 Train A General 2 Product B Tablet Method 1 Train B General 3 Product C Parenteral Method 2 Train C Cytotoxic 4 Product D Tablet Method 3 Train B General 5 Product E Tablet (EC) Method 4 Train A General 6 Product F Parenteral Method 2 Train C Cytotoxic 7 Product G Tablet (FC) Method 1 Train A Cytotoxic 8 Product H Tablet Method 3 Train B General 9 Product I Tablet (EC) Method 4 Train A General 10 Product J Parenteral Method 2 Train C Cytotoxic Before Grouping : Quality Assurance
  26. 26. CLEANING VALIDATION…….……GROUPING STRATEGIES 25 Sr. No. Name of product Formulation Cleaning methods Equipment train Risk / Therap. class 1 Product A Tablet (FC) Method 1 Train A General 2 Product B Tablet Method 1 Train B General 3 Product G Tablet (FC) Method 1 Train A Cytotoxic 4 Product C Parenteral Method 2 Train C Cytotoxic 5 Product F Parenteral Method 2 Train C Cytotoxic 6 Product J Parenteral Method 2 Train C Cytotoxic 7 Product D Tablet Method 3 Train B General 8 Product H Tablet Method 3 Train B General 9 Product E Tablet (EC) Method 4 Train A General 10 Product I Tablet (EC) Method 4 Train A General After Grouping : Quality Assurance
  27. 27. CLEANING VALIDATION…..WORST CASE CONSIDERATIONS Once the product groups have been established, the next step is to determine the so-called “worst case” representative of each group. It is that member(s) who shows the highest challenge on cleaning program. Worst case product : Toxicity / solubility / highly characterized / difficult to clean ingredients. Worst case eq. train : Longest train. Worst case equipment : Larger size equipment (identical design). Worst case acc. criteria: Stringent acceptance criteria. Hold time studies : Longest possible duration. Campaign Mfg. : Highest possible nos. of batches. 26 Quality Assurance
  28. 28. CLEANING VALIDATION…..WORST CASE CONSIDERATIONS There is no ‘hard & fast’ rule on worst case selection. A good logic and science should always be used. Grouping and worst case selection help to demonstrate cleaning method robustness. It smartly reduces the load from cleaning validation program. These philosophies should always be verified against the actual capability of cleaning program. The ultimate ‘cost – benefit’ ratio should be evaluated. 27 Quality Assurance
  29. 29. CLEANING VALIDATION…………...ACCEPTANCE CRITERIA 28 How clean is clean ? What are the bases of defining limits ? What are the impacts of after cleaned residue ? Human Drug CGMP Notes, 9:2, 2Q 2001 : “Should equipment be as clean as the best possible method of residue detection or quantification?” Answer: “No,……absolute cleanliness is neither valuable nor feasible…. It should be as clean as can be reasonably be achieved, to a residue limit that is medically safe and that causes no product quality concerns…………….” Quality Assurance
  30. 30. Three criteria :  It should be scientifically justifiable.  Pacifically achievable.  Methodically verifiable. 29 Possible types of limits :  Visual  Chemical  Microbiological  Endotoxin CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Quality Assurance
  31. 31. Visual clean criteria : GMPs require inspection for visual cleanness before manufacture. Key items to consider : o Angle of view o Distance from equipment surface o Lighting conditions o Viewer’s knowledge o Surface usually must be dry Visual aids : Additional lighting / Magnifying glass / Mirror / Fiber-optic scope / UV light 30 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Quality Assurance
  32. 32. Application for visual limits : A typical visual limit is NLT 4 μg / cm2. “Visually clean” may not be enough by itself  Potent drugs  Microbial contamination  Endotoxin More suitable method for non-potent drug products and APIs. PIC/S advocates spiked coupon study for determination of visual inspection limits (and for training of inspectors). 31 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Quality Assurance
  33. 33. Chemical residue limits (Therapeutically or Toxicologically safe criteria) :  Therapeutic dose based criteria Most suitable for drug product (finished product) manufacturing facility.  Toxicological criteria Most suitable for active drug (API) manufacturing facility. Where cleaning agents are used (other than water).  10 PPM criteria CGMP requirement widely applicable. 32 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Quality Assurance
  34. 34. Therapeutic dose based criteria : Based on the assumption that 1/1000 part of therapeutic dose does not have any clinical impact on human (animal) body. Determination of MAC (Maximum Allowable Carryover) of Product A (Previous) to Product B (Next) SRDD (A) × BS (B) × SF MAC = (unit of mass) LRDD (B) Where, SRDD = Smallest Recommended Daily Dose (Product A – ACTIVE CONTENT), BS = batch size (Product B), SF = safety factor and LDD and LRDD = Largest Recommended Daily Dose (Product B – DRUG PRODUCT) 33 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 1 Quality Assurance
  35. 35. Therapeutic dose based criteria : Determination of Surface contamination (Shared Equipment) MAC L1 = (mass / surface area) SESA Where, SESA = Shared Equipment Surface Area (for both products) 34 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 2 Quality Assurance
  36. 36. 35 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 3 Therapeutic dose based criteria : Determination of Sampled residue (for swab sample) L2 = L1 × Swab Area (mass / swab)  SRDD value represents the ACTIVE drug content only. e.g. 5 mg or 10 mg, the dose strength.  LRDD value represents the mass or volume of entire dose. e.g. 250 mg or 20 mL (drug + excipients).  Convert similar items into similar convenient unit of measure. Quality Assurance
  37. 37. Safety Factors : 36 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Approach Approach Typically Applicable To 0.1 to 0.01 Topical products 0.01 to 0.001 Oral products 0.001 to 0.0001 Parenterals, opthalmic products 0.0001 to 0.00001 Research, investigational products Quality Assurance
  38. 38. 37 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 1 Therapeutic dose based criteria (an example) : Determination of Maximum Allowable Carryover 10 mg × 150 kg × 0.001 × 1000000 (250 mg × 3) = 2000 mg (MAC value) Quality Assurance
  39. 39. 38 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 2 Therapeutic dose based criteria (an example) : Determination of Surface contamination level 2000 mg 3170 cm2 = 0.63 mg / cm2 (L1 value) Quality Assurance
  40. 40. 39 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 3 Therapeutic dose based criteria (an example) : Determination of Swab residue 0.63 mg / cm2 × 25 cm2 = 15.75 mg / swab (L2 value) Quality Assurance
  41. 41. Toxicological criteria : Based on the toxicological information available in Material Safety Data Sheets. Determination of NOEL (No Observed Effect Level) NOEL = LD50 × Emperical Factor (unit of mass/kg of body weight) Where, LD50 = lethal dose for 50% of animal population in study (mg/kg/day), Emperical Factor = derived from animal model developed by Layton, et.al : 0.001* * Used by expert panel of WHO (10-3). 40 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 1A Quality Assurance
  42. 42. Toxicological criteria : Determination of ADI (Acceptable Daily Intake) ADI = NOEL × AAW × SF (unit of mass) Where, AAW = average adult weight : 70 kg, SF = safety factor (0.01) 41 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 1B  Consider average body weight of child where there is any pediatric dose available.  Use LD50 value of mice. Quality Assurance
  43. 43. Toxicological criteria : Determination of MAC (Maximum Allowable Carryover) ADI × BS MAC = LRDD (any next product) (unit of mass) Then use and to derive final swab residue limit. 42 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 1C Step 2 Step 3 Quality Assurance
  44. 44. 43 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 1A Toxicological criteria (an example) : Determination of NOEL (1750 mg /kg/day) × 0.001 = 1.75 mg/kg (NOEL value) Determination of ADI (1.75 mg/kg) × 70 kg × 0.01 = 1.225 mg (ADI value) Step 1B Quality Assurance
  45. 45. 44 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 1C Toxicological criteria (an example) : Determination of MAC 1.225 mg × 150 kg × 1000000 (250 mg × 3) = 245000 mg The final Swab residue (L2) : 245000 mg × 25 cm2 3170 cm2 = 1932 mg/swab Quality Assurance
  46. 46. 10 PPM criteria : Based on the hypothesis that 10 parts of previous product is therapeutically ineffective if presents in million parts of next product. Determination of MAC 10 × BS MAC = (unit of mass) 1000000 Where, BS = batch size (smallest available batch size) Then use and to derive final swab residue limit. 45 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 1 Step 3Step 2 Quality Assurance
  47. 47. 46 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Step 1 10 PPM criteria (an example) : Determination of MAC 10 × 150 kg × 1000000 MAC = = 1500 mg 1000000 The final Swab residue (L2) : 1500 mg × 25 cm2 3170 cm2 = 11.83 mg/swab Quality Assurance
  48. 48. 47 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA The most stringent acceptance criteria shall be chosen for cleaning validation study (The worst case approach). 11.8315.75 1932 mg / swab In real life cases, therapeutic or 10 PPM criteria become final acceptance criterion for cleaning validation. Quality Assurance
  49. 49. Microbiological criteria :  Internal specifications  Official specifications: e.g. USP <1111>, “Microbial Examination of nonsterile Products: Acceptance criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use” 48 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Adminstration route Total aerobic count (cfu/g or cfu/mL) Total combined yeasts/molds count (cfu/g or cfu/mL) Nonaqueous oral 103 102 Aqueous oral 102 10 Most topicals 102 10 Quality Assurance
  50. 50. Microbiological criteria :  Environmental specifications: EU GMP, Annex – 1, “Recommended limits for microbiological monitoring of clean areas during operation” 49 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Grade Contact plates (diam. 55 mm), cfu/plate A < 1 B 5 C 25 D 50 i.e. recommended limit for microbial contamination in grade D area is : 50/{π × (5.5/2)2}= 2.10 cfu/cm2 Quality Assurance
  51. 51. Microbiological criteria from internal specifications:  Driven by SOP.  Must be backed up by justifiable scientific rationale. Microbiological criteria from official specifications: Spec. limit × factor × Wt. product SESA An example: 1000 cfu/g × 0.1 × 5 kg × 103 3170 cm2 50 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA × swab area × 25 cm2 = 3943 cfu/swab Quality Assurance
  52. 52. Microbiological criteria from environmental specifications: 50/{π × (5.5/2)2} × swab area An example: 2.10 cfu/cm2 × 25 cm2 = 52 cfu/swab 51 CLEANING VALIDATION…………...ACCEPTANCE CRITERIA Quality Assurance
  53. 53. Determining acceptance criteria with more than one next products (The Matrix approach): CLEANING VALIDATION…………...ACCEPTANCE CRITERIA NEXT PRODUCT Prod. A Prod. B Prod. C Prod. D Prod. E (kg) B. Size 200.0 75.0 100.0 150.0 355.5 (cm2) S. Area 4525 3960 4015 3770 4008 (mg) SRDD LRDD GENERAL SOLID FACILITY Product A 10.0 450.0 10.5 13.8 22.1 49.3 Product B 1.0 320.0 3.4 1.9 3.1 6.9 Product C 25.0 600.0 46.0 19.7 41.4 92.4 Product D 5.0 300.0 18.4 7.9 10.4 36.9 Product E 125.0 800.0 172.6 74.0 97.3 155.4 52 PREVIOUS PRODUCT Quality Assurance
  54. 54. The sampling procedure refers to the method of collecting the residues from the surface so that they can be measured. CLEANING VALIDATION…………......SAMPLING METHODS Types Advantages Limitations Swabs & Wipes Dissolves & physically removes sample, adaptable to wide variety of area May introduce fibers, technique dependent, hard-to- reach areas Rinse Easy, quick, non-intrusive, large surface area Limited information about actual surface cleanliness Coupon Non-technique dependent, reduces variability in recovery Invasive, might interfere with cleaning process Placebo Placebo contacts the same surfaces as the product Difficult to determine recovery Direct Surface Rapid, non-invasive, economical Some techniques not widely developed 53 Quality Assurance
  55. 55.  Swab sampling techniques: (1) One of the most widely used technique for chemical and microbial sampling. (2) Swabs are being wet with solvent aiding solubilization and physical removal of surface residues. (3) Results are technique dependent. CLEANING VALIDATION…………......SAMPLING METHODS 54 Microbial swab (sterile) Chemical swabs (Texwipe) Cotton wipes Quality Assurance
  56. 56.  Swab sampling techniques: (5) Generally 1 swab sample per location is adequate. (6) Multiple swabs can be taken to improve surface recovery. (7) Typical swabbed per site varies from 25 cm2 to 100 cm2. There is no “magic” number. (8) PTFE (chemically inert) templates may be used for accurate swabbing area. (9) “Difficult to clean” equipment surfaces shall be identified and sampled. (10) Representative surfaces of different materials (MOCs) should be sampled. CLEANING VALIDATION…………......SAMPLING METHODS 55 5 cm 5 cm 2.5 cm 10 cm Swab area templates Quality Assurance
  57. 57.  Swab sampling techniques: (11)Wiping should be unidirectional at a time. Parallel strokes should be employed to cover entire swab area. CLEANING VALIDATION…………......SAMPLING METHODS 56 Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc Quality Assurance
  58. 58.  Swab sampling techniques: Example of “Difficult to clean” locations of an RMG: CLEANING VALIDATION…………......SAMPLING METHODS 57 Courtesy: Rapid mixer granulator, Kevin. The design aspect of the equipment should be considered to identify “difficult to clean” locations. Quality Assurance
  59. 59.  Rinse sampling techniques: Rinse sampling involves using a liquid to cover the surfaces to be sampled. (1) One of the easy and widely used sampling method. (2) Most preferable liquid for rinsing is water. (3) The rinse volume is an important factor that has to be determined. Rinse volume α (1/Residue conc. in rinse sample) (4) Forced rinsing is advisable for collection of less soluble residues. CLEANING VALIDATION…………......SAMPLING METHODS 58 Quality Assurance
  60. 60.  Determination rinse volume: (1) Variability in magnitudes of surface areas gives rise of variable residue concentrations in rinse samples (fixed rinse volume). (2) Variable acceptance criteria for a single product creates confusion. (3) It is a good idea to chose variable rinse volumes to keep constant residue concentration in rinse samples (fixed acceptance criteria). Formula : L1 × ESA Rinse vol. for Equipment A = Anticipated rinse conc. CLEANING VALIDATION…………......SAMPLING METHODS 59 Quality Assurance
  61. 61.  Determination rinse volume: Example : 0.63 mg / cm2 × 1760 cm2 Rinse vol. for Equipment A = 10 μg / mL = 110.9 L (considering mg/L = PPM) 0.63 mg / cm2 × 810 cm2 Rinse vol. for Equipment B = 10 μg / mL = 51.0 L CLEANING VALIDATION…………......SAMPLING METHODS 60 Quality Assurance
  62. 62.  Specific vs non-specific methods: (1) A non-specific assay may detect a variety of residues. (2) A specific assay may quantify any anticipated residue. (3) It is essential to correlate the results from a specific method to the results from other non-specific methods that might be used for routine monitoring of cleaning effectiveness. CLEANING VALIDATION…………ANALYTICAL METHODS 61 HPLC pH meter Quality Assurance
  63. 63. CLEANING VALIDATION…………ANALYTICAL METHODS 62 Specific Test Methods Non-Specific Test Methods UV/Visible Spectrophotometry Near Infrared Spectrophotometry (NIR) High Performance Liquid Chromatography (HPLC) Mid Infrared Spectrophotometry (MIR) Atomic Absorption Capillary Zone Electrophoresis Enzyme Linked Immunosorbant Assay (ELISA) Total Organic Carbon (TOC) pH Titration Conductivity Gravimetric Quality Assurance
  64. 64. The analytical methods used for testing cleaning samples must be validated for [ICH Q2 (R1)]:  Limit of Detection (LOD)  Limit of Quantification (LOQ)  Specificity  Accuracy  Repeatability  Precision  Range  Linearity  Recovery CLEANING VALIDATION…………ANALYTICAL METHODS 63 Quality Assurance
  65. 65.  The analytical method used for evaluation of cleaning sample is different that used for product assay.  If the target limit in the analytical sample were 5.2 μg / mL, and a method was only able to detect down to 7.0 μg / mL, that method would not be useful for cleaning validation purposes.  The target value should be within the linearity range of the specific method. What if the calculated acceptance value is less than the detectable level of an analytical method? There may be two options available………. CLEANING VALIDATION…………ANALYTICAL METHODS 64 Quality Assurance
  66. 66. Choose more efficient analytical method ! Example: Derived acceptance limit = NMT 4.0 μg / mL Analytical LOQ = 5.5 μg / mL Analytical Method = UV/Visible Spectrophotometry New method adopted = Ion mobility spectrometry New LOQ = 2.0 μg / mL CLEANING VALIDATION…………ANALYTICAL METHODS 65 Quality Assurance
  67. 67. Increase the sampling area to achieve at least LOQ value! Example: Derived acceptance limit = NMT 4.0 μg / mL Analytical LOQ = 5.5 μg / mL Swab area = 25 cm2 CLEANING VALIDATION…………ANALYTICAL METHODS 66 Revised swab area = 25 cm2 4.0 μg / mL × 5.5 μg / mL = 35 cm2 (7 cm × 5 cm) Quality Assurance
  68. 68. Recovery studies : Procedure : o Spike coupon with known amount o Allow to dry o Remove in swab or simulated rinse procedure o For swab, desorb o Analyze sample o Compare to expected 100% value This is done at surface acceptance (or below) limit. CLEANING VALIDATION…………ANALYTICAL METHODS 67 Quality Assurance
  69. 69. Swab recovery schematic : CLEANING VALIDATION…………ANALYTICAL METHODS 68 1. Spike control diluent directly Control B μg/mL Control C μg/mL Standard solution A μg/mL 2a. Spike coupon 2b. Swab coupon 2c. Extract swab Quality Assurance
  70. 70. Recovery calculation 1 (Spiked against Standard): (C μg/mL) × (mL) % Recovery = × 100 (A μg/mL) × (mL) CLEANING VALIDATION…………ANALYTICAL METHODS 69  Recovery depends on spiked standard of known concentration.  Disorbing solvent may be of any volume (mL).  Recovery depends on material surface, sampling method and some what on analytical method. Quality Assurance
  71. 71. Recovery calculation 2 (Spiked against Positive control) : (C μg/mL) × (mL) % Recovery = × 100 (B μg/mL) × (mL) CLEANING VALIDATION…………ANALYTICAL METHODS 70  More useful if defined standard is not readily available. Swab recover study with multiple analysts :  Usually 3 replicates by one sampler.  Use lowest value of any one run. Quality Assurance
  72. 72. Rinse recovery schematic : CLEANING VALIDATION…………ANALYTICAL METHODS 71 Pipette with rinse solution (known volume) Spiked coupon Collection beaker Spike bottom of SS beaker Lab sheker Case 1 Case 2 Quality Assurance
  73. 73. Minimum acceptable recovery:  Specify in cleaning validation master plan or master protocol.  Minimum swab recovery of 70 % - 80 %.  Minimum rinse recovery of 50 %.  Carry out recovery study for different material surfaces (Material Of Constructions).  Chose right wetting solvent (soluble) and absorbent swab material to improve recovery.  May allow <50 % recovery with written justification. CLEANING VALIDATION…………ANALYTICAL METHODS 72 Quality Assurance
  74. 74. o DEHT = Max. allowed time, between end of usage and employing cleaning o CEHT = Max. allowed time, between end of cleaning and further usage CLEANING VALIDATION………………………HOLD TIMES 73 Cleaning Hold Time studies Cleaned Equipment Hold Time (CEHT) Dirty Equipment Hold Time (DEHT) Quality Assurance
  75. 75. Dirty equipment hold time study (DEHT) :  Soils may become more difficult to clean over time.  Maximum DEHT should be in SOPs.  Maximum time shall be set in conjunction with production.  Representative / worst case product can be selected for study.  Equipments support wet processing can be selected.  If extra cleaning is desirable, then it should be in SOP.  May be expressed in days but preferably by hours.  Three runs at maximum time……..safe harbor. 74 CLEANING VALIDATION………………………HOLD TIMES Quality Assurance
  76. 76. Dirty equipment hold time study (DEHT) : Method  Carry out microbiological sampling at 24 hr., 48 hr., 36 hr., …... from the dirty equipments.  Clean the equipments as per SOPs.  Carry out chemical sampling after cleaning.  Compile all results (chemical and microbial).  Successful results shall standardize the maximum DEHT.  Failure of any results shall reduce the max. DEHT followed by another 3 verification runs. 75 CLEANING VALIDATION………………………HOLD TIMES Quality Assurance
  77. 77. Cleaned equipment hold time study (CEHT) :  Microbiological evaluation is the key focus area.  Maximum CEHT should be in SOPs.  Representative / worst case product can be selected for study.  Vitamins, nutritional supplements, product containing Starch or Gelatin may represent worst cases.  Avoid conducting study on antibiotic or antimicrobial products.  Three runs at maximum time……..safe harbor.  Protection during storage of cleaned equipments should be as per SOPs. 76 CLEANING VALIDATION………………………HOLD TIMES Quality Assurance
  78. 78. 77 Cleaned equipment hold time study (CEHT) : Method  Clean the equipments as per SOPs.  Store under protection (as per routine procedure).  Carry out microbiological sampling at 24 hr., 48 hr., 36 hr., …...  Verify the results against limit (less than validation limit).  Successful results shall standardize the maximum CEHT.  Failure of any results shall reduce the max. CEHT followed by another 3 verification runs.  Do not set max. CEHT on “until failure” basis. CLEANING VALIDATION………………………HOLD TIMES Quality Assurance
  79. 79. 78 Campaign hold study (CHS) :  Cleaning after production of definite number consecutive batches.  Negotiate with production related to number of batches.  Simulate max. anticipated hours of campaign production.  Cumulative deposition of residues may accelerate product degredation.  Perform cleaning and sampling at the end of campaign.  Max. CHS (no. of batches + time) should be in SOPs.  Batch to batch or lot to lot cleaning is advisable.  More suitable for dedicated product equipments. CLEANING VALIDATION………………………HOLD TIMES Quality Assurance
  80. 80. CLEANING VALIDATION……………....ALL ASPECTS OF CV 79 Courtesy: Biopharm international Quality Assurance
  81. 81. CLEANING VALIDATION…………USFDA 483 CITATIONS Cleaning Parameters “….. cleaning of ….. has not been validated, nor is the spray temperature, volume or time defined.” 80 Quality Assurance
  82. 82. CLEANING VALIDATION…………USFDA 483 CITATIONS Time of Cleaning “Equipment cleaning is performed on a “clean until clean” basis. There has been no determination of the number of cleanings required to ensure the cleanliness of the equipment.” 81 Quality Assurance
  83. 83. CLEANING VALIDATION…………USFDA 483 CITATIONS Manual Cleaning “Hands on training for equipment cleaning operations is not provided and there is no program in place to assure cleaning consistency between operators.” 82 Quality Assurance
  84. 84. CLEANING VALIDATION…………USFDA 483 CITATIONS Cleaning Log “There is no assurance that cleaning is conducted as stated in their SOPs…… There are no cleaning logs to indicate that this has been done.” 83 Quality Assurance
  85. 85. CLEANING VALIDATION…………USFDA 483 CITATIONS Poor Cleaning “….. we observed foreign material on the filter grates….. Daily cleaning as per SOP…..failed to remove the material. End of process cleaning as per SOP…..failed to remove the material. Weekly cleaning as per SOP……failed to remove the material.” 84 Quality Assurance
  86. 86. CLEANING VALIDATION…………USFDA 483 CITATIONS Detergent Concentration “Detergent is dispensed into the ……Stopper Washer reservoir every third cycle. No data has been collected to determine the detergent concentration each cycle…..” 85 Quality Assurance
  87. 87. CLEANING VALIDATION…………USFDA 483 CITATIONS Cleaning Agent Labeling “The firm’s control over IPA 100% used to clean equipment in production is inadequate. …..bottles are not labeled…..with date, expiration or who dispensed, ….no scientific information….which would establish an expiration date…..” 86 Quality Assurance
  88. 88. CLEANING VALIDATION…………USFDA 483 CITATIONS Acceptance Limit “….. acceptance criteria….shall not exceed…..μg/cm2. There is no data to justify this limit.” 87 Quality Assurance
  89. 89. CLEANING VALIDATION…………USFDA 483 CITATIONS Sampling Locations “Swabbing was performed on general contact areas without taking into consideration area such as edges and crevices.” 88 Quality Assurance
  90. 90. CLEANING VALIDATION…………USFDA 483 CITATIONS Sampling Locations “Exact / precise swab locations are not identified.” 89 Quality Assurance
  91. 91. CLEANING VALIDATION…………USFDA 483 CITATIONS Swab Sampling “Swab samples collected…..from different locations from each piece of equipment are combined into one sample and tested such.” 90 Quality Assurance
  92. 92. CLEANING VALIDATION…………USFDA 483 CITATIONS Rinse Sampling “….firm’s validation…..is inadequate in that the rinse solutions were not analyzed for the presence of the active ingredient residues that might be present.” 91 Quality Assurance
  93. 93. CLEANING VALIDATION…………USFDA 483 CITATIONS Rinse Sampling “There is not an exact sampling procedure for the collection of rinse water samples which takes into account the surface area involved, time of contact….., volume of rinse, and temperature of rinse, along with a formula to calculate the amount of possible contamination based on analysis.” 92 Quality Assurance
  94. 94. CLEANING VALIDATION…………USFDA 483 CITATIONS Dirty Equipment Hold Time “No time frames / limitations have been established for production equipment from end of use to start cleaning.” 93 Quality Assurance
  95. 95. CLEANING VALIDATION…………USFDA 483 CITATIONS Cleaned Equipment Hold Time “A time limit for the length of time allowed between cleaning and the use of the manufacturing equipment…..has not been established.” 94 Quality Assurance
  96. 96. CLEANING VALIDATION…………USFDA 483 CITATIONS Recovery Studies “Equipment cleaning validation studies for…..did not include…..present recovery studies on rinse samples.” 95 Quality Assurance
  97. 97. CLEANING VALIDATION…………USFDA 483 CITATIONS Recovery Studies “…..each drug’s recovery test was performed only once, therefore there is no data to show reproducibility.” 96 Quality Assurance
  98. 98. CLEANING VALIDATION…………USFDA 483 CITATIONS Recovery Studies “Your firm is using the average of recovery results (from different amounts of spiked solution) instead of the worst case result. Using a value that represents the average does not ensure that contamination is not higher than calculated.” 97 Quality Assurance
  99. 99. CLEANING VALIDATION…………USFDA 483 CITATIONS Change Control “The SOP has been revised twice. No review was performed to determine if a re-validation was necessary for the changes……” 98 Quality Assurance
  100. 100. CLEANING VALIDATION……………................................??? Quality Assurance
  101. 101. CLEANING VALIDATION……...SOURCES OF INFORMATION  “Guide to Inspections Validation of Cleaning Processes”, Inspection note by FDA (US).  “Recommendation on VMP, IQ and OQ, non-sterile process validation and cleaning validation”, (PIC/S).  “GMP guide for API”, (ICH, Q7).  “Guidance on Cleaning Validation”, Health Canada. Technical sources :  Points to Consider for Cleaning Validation, PDA 29.  Points to Consider for Biotechnology Cleaning Validation, PDA 49 Sambhujyoti Das, Quality Assurance 100
  102. 102. CLEANING VALIDATION

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