Pharmaceutical Equipment Validation: IQ, OQ, PQ, Cleaning, and Process Control Guidelines

Validation is the backbone of pharmaceutical quality assurance. This deck covers equipment qualification (DQ, IQ, OQ, PQ), analytical method validation, process validation, and cleaning validation. It explains calibration procedures, vendor qualification, process utilities (water systems, HVAC, steam, compressed air), and facility validation. It also details FDA, WHO, and GMP expectations, highlighting how validation minimizes risks, ensures safety, and reduces quality costs. This content is essential for students preparing for roles in quality assurance, production, and regulatory audits.
Validation is a critical aspect of pharmaceutical quality assurance, ensuring that processes, equipment, and facilities consistently deliver products meeting predefined standards. This presentation explains validation types (analytical, equipment, cleaning, process), along with protocols such as IQ, OQ, PQ, and DQ. It also covers calibration, raw material/vendor qualification, process utilities (water, steam, HVAC, compressed air), facility validation, product design, and operator training. Students will learn about FDA definitions, WHO guidelines, and industry practices to minimize errors, reduce costs, and ensure patient safety. The content is highly useful for M.Pharm students in pharmaceutics, regulatory affairs, and quality assurance, as well as industry trainees.

1. VALIDATION Presented by Ayushi Jain M-Pharmacy

2. Validation Introduction : Validation means rectification or confirmation. It is the concept which establishes a documented program of specified & reliable performance. Definition : According to U.S.F.D.A., “ Validation is a documented p rogramme, which provides a high degree of assurance that a specific process will consistently produce, a product meeting its predetermined specification & quality attributes”. 2

3. Scope of validation: Pharmaceutical Validation is a vast area of work & it practically covers every aspect of pharmaceutical activities. 3

4. Scope of validation: Analytical test method: The analytical test method requires demonstration of the following characteristics in it. Ex:- Accuracy Precision Specificity Limit of detection Limit of quantitation Linearity Range Ruggedness robustness 4

5. Instrumentation calibration: Measurement of various parameters is a prime activity in processing & hence, it demands a very high level of accuracy in such measurements. Some of the common measurements involved are temperature, time, humidity, pressure, conductivity, time, rotations, current, voltage, pH, volumes, weights & soon. All such parameters are calibrated so that a level of confidence in the measurements & also in the process becomes high. Process utility services: Supports manufacturing process & plant is required to operate them regularly. Some of the important process utility services are as follows: Different types of water- raw water Raw water. Potable water. Soft water. Purified water. Water for injection. 5

6. Steam Plant steam. Pure steam. HVAC System Heating. ventilation. Air conditioning. Compressed air Different gases Nitrogen. L.P.G. Oxygen. Carbon di oxide. Drainage system The validation of these process utilities constitute the following phases ex: Design phase, installation, commissioning, challenge & monitoring. 6

7. Raw materials & packaging materials: Qualification requires two phases Stage 1: defining specification for each & every item of R.M/P.M. Such that it meets the product & process requirements. It may also require to meet the pharmacopieal requirements as well. Stage 2: vendor certification- to study & certify the vendor who can supply you the desired quality of materials, in required quantities at expected time & at affordable price. Equipment: Done as follows : URS, FRS ( Functional Requirement Specification), DQ, IQ, PQ. Needs Protocol for each steps. The equipment should also covers the S.O.P. identification & verification for cleaning, operation, & maintenance of the equipment's. 7

8. Facilities: Qualification of pharmaceutical facilities involve the following phases namely: Defining user requirements in term of user requirements specifications. Functional requirements specifications. Deriving design qualification. Construction of the facilities. Certification of constructed facility. Ongoing building maintenance . Manufacturing: Pharmaceutical formulation is divided into dosage form. Each dosage form has various process & should be validated. Ex: tablet – which involves dispensing, sifting of raw materials, milling, mixing, compression, granulation , filling, bulk preparation, packaging ( blister, strip, general ), dispatching, pre formulation tests, post formulation tests, finished goods . 8

9. Product design: It is the 1 st stage in pharmaceutical validation process. Involves Formulation development. Primary package compatibility/studies. Defining specification for R.M/P.M. Defining the process & qualifying the same. Quality control specifications & test methods. Pilot plant studies. Trial commercial batches/ prospective validation. Commercial production. Concurrent validation. Revalidation. 9

10. Cleaning : Involves mainly 3 areas namely: Equipment & process containers. Product containers/closures. Facility. Cleaning validation should also cover the following points namely- Cleaning limits ( expected level of cleaning). Materials used for cleaning. Cleaning methods. Trace analysis, method & limits. Frequency of cleaning wherever applicable. 10

11. Operators: It is a vital link in whole validation process. Training is very important role and it involves 3 factors namely: Knowledge: technical, GMP related, safety, hygiene supervisory, productivity etc. Skills: technical, safety & skill to apply the available knowledge in other areas. Attitude: a positive & constructive attitude towards every work he is doing. 11

12. Importance of validation: Every activity in any Business unit is done to get some benefit from that, and naturally pharmaceutical validation is no exception. This means validation activity must give the industry some advantages, some benefits & some added value. Dr. Robert G. Keifer of sterling International group, Sterling Drug Incorporation New York U.S.A., has described the advantages of validation. Reduction of Quality Costs. Process Optimization. Assurance of Quality. Safety. 12

13. Reduction of quality costs Its quality cost about 10-15 % of total manufacturing costs. Preventive costs: costs incurred in order to prevent failures &/or reduce appraisal costs. Involves:- Quality planning Vendor approval system Training Documentation, SOP, monographs Preventive maintenance Calibration Sanitation Process validation QA auditing & self inspection Annual review of data or trend analysis. 13

14. b. Appraisal costs: Costs of inspection, testing & quality evaluation. Examples involves:- Inspection / testing raw & packaging materials. Inspection / testing of in process materials. Inspection / testing of finished products. Stability testing. c . Internal failure costs: costs associated with non-confirming materials that does not meet quality standards, still in the company’s possession. Examples involves:- Rejects Reworks Re-inspection Retests Wastage/scrap Sorting substandard materials. 14

15. d. External failure costs: costs associated with a non conformance condition after the product has left the company’s ownership. Examples involves:- Recalls Complaints Returns due to quality related problems. 2.Process optimization: Means make the process effective, efficient, perfect or useful as possible at the minimum cost. Trained qualified people are key element and the persons are trained as per GMP training guidelines. Ex:-a) reduced sterilization time due to studies of bio burden validation & sterilisation of autoclave. b) reduced overfilling of liquids due to filling equipment. 15

16. 3. Assurance of quality: Validation is a extension part of quality assurance. It is a heart of GMPs. End product testing in the absence of validated processes gives little assurance of quality for various reasons ex:- Very limited sample size The limited number of tests performed on a sample Limited sensitivity of the tests. 4.safety: Validation can also result in increased operation safety ex:- gauges used on equipment that is designed to operate at certain temperatures & pressures must be reliable i.e. they must be calibrated. 16

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18. Types of validation: Analytical method validation. Equipment validation. Cleaning validation. Process validation. 18

19. 1. Analytical Method Validation: Method validation must prove that the analytical method used for a specific test is suitable for which it is to be carried out. Methods should be validated when- When they are to be established for routine use. when the method is to be changed due to change in conditions. whenever the equivalence between new method & the standard are demonstrated. 19

20. Types of procedures to be validated: a) Accuracy: The accuracy of analytical method refers to the closeness of agreement between the observed value & the value which is either conventionally a true one or reference one. b) precision: The precision of an analytical method refers to the closeness of values obtained from a series of tests. c) Repeatability: Repeatability is established when the same sample is estimated repeatedly by the same analyst using same analytical method within the same laboratory using same instrument & performed within a short period of time. 20

21. d) Intermediate Precision : When the test is repeated on different days by different persons or using different instruments within the same laboratory, the variation is expressed in terms of intermediate precision. e) Reproducibilty : When a mixed is standardized, the test is carried out in different laboratories using the same method, the precision between the laboratories is referred to as reproducibility. f) Specificity: Specificity is the ability of a test method to measure the analyte explicitly in the presence of other components. 21

22. g) Linearity : Linearity of an analytical method refers to its ability to measure a specific component within a range. h) Detection Limit: The lowest amount of analyte in a sample that can be detected but not necessarily quantitated, under the stated experimental conditions. i ) Quantitation Limit: A characteristic of quantitative assays for low levels of compounds in sample matrices such as impurities in bulk substance & degradation products in finished pharmaceuticals. It is the lowest amount of analyte in a sample that can be determined with acceptable precision & accuracy under the stated experimental conditions. 22

23. j) Robustness: A measure of its capacity to remain unaffected by small but deliberate variations in method parameters & provides an indication of its reliability during normal usage. k) Range: Interval between the upper & lower of analyte that have been demonstrated to be determined with a suitable level of precision , accuracy and linearity It is expressed as percentage parts per million obtained by analytical method. 23

24. 2. Equipment Validation: It is to provide a high level of documented evidence that the equipment & the process confirm to a standard. Types : a) Installation Qualification. b) Operation Qualification. c) Design Qualification. d) Performance Qualification. 24

25. 3. Cleaning Validation: It ensures that there is no cross contamination In a multi product manufacturing plant & also prevents microbial contamination. Once a product is manufactured equipment, the equipment is cleaned using appropriate cleaning SOP'S established during IQ of the equipment. Types of contamination to be considered in cleaning validation- a) Cross Contamination. b) Microbial Contamination. c) Contamination by cleaning or sanitizing agent. d) Contamination by other agents. 25

26. 4. Process Validation : It is the means of ensuring & providing documentary evidence that the processes are capable of repeatedly & reliably producing a finished product of the required quality. Types of process validation- a) Prospective Validation. b) Concurrent Validation. c) Retrospective Validation. d ) Process Revalidation. 26

27. Prospective Validation: Also called as premarket validation . Carried out prior to distribution of new product or existing product made under a revised manufacturing processes where such revision may affect product specification or quality characteristic. In this an experimental plan called the validation protocol is executed before the pocess is put into commercial use. This particular type of process validation is normally carried out in connection with the introduction of new drug products and their manufacturing processes. 27

28. Concurrent Validation: Study is carried out under a protocol during a course of normal production. It gives assurance of present batch being studied and offer limited assurance regarding consistency of quality from batch to batch. This may be practical approach under certain circumstances. ~ when previously validated process is being transferred to a 3 rd party contract manufacturer or to another manufacturing site. ~ where the product is a different strength of a previously validated product with the same ratio of active/inactive ingredients. 28

29. Retrospective Validation: Conducted for a product already marketed and its based on extensive historical data accumulated over several lots and over time. Some essential elements are: Batches manufactured for a defined period. Batch size/strength/ manufacturer/year. Master manufacturing /packaging documents. Current specifications for active materials/finished products. List of process deviations, corrective actions & change to manufacture documents. Data for stability testing for several batches. 29

30. Revalidation: All or a portion of validation ie required to be repeated when changes that affect original validation are made. examples: Changes to product specifications. Process parameters. equipment( type, function, location, control system, major repairs). Raw materials. Manufacturing materials. Packaging materials. 30

31. WHO GUIDELINES FOR CALIBRATION AND VALIDATION OF EQUIPMENTS 31

32. VALIDATION OF EQUIPMENTS Equipment is one of the basic component of the P harma I ndustry, hence before validating a process it is carried out. The issue of equipment validation becomes prime importance. Equipment validation process generally covers the following steps: a. Customer Requirements or User Requirement Specifications. b. Preparation of Design Qualification &its certification. c. Installation Qualification. d. Operational Qualification. e. Performance Qualification. 32

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34. Principle Equipment must be Located Designed Constructed Adapted Maintained to suit the operations to be carried out. 34

35. Equipment layout and design must aim: –to minimize risk of error. –to permit effective cleaning and maintainence . To Avoid: –cross contamination, dust & dirt built up. –any adverse effect on the quality of products. Equipment must be installed to: –minimize risk of error. – minimize risk of contamination . 35

36. Control laboratory equipment Equipment and instruments- Suitable for the Tests to be performed. Defective equipment- Removed. Labelled. Washing ,cleaning and drying- Equipment must not be source of contamination. Equipment design should promote easy cleaning. Cleaning on daily basis, schedules, procedures & records. 36

37. The content of equipment qualification Application S.O.P's Utilization list Process description Test instrument utilized to conduct test Test instrument calibration Critical parameters test function(list) Test function summaries 37

38. Qualification policy for system and Equipment's: To include instruments used in production and quality control. New systems and equipment's: All stages of qualification applicable(DQ,IQ,OQ,PQ). Qualification should be done in accordance with predetermined and approved qualification protocols. The results of the qualification should be recorded and reflected in qualification reports. 38

39. Calibration and validation of Equipment's 39

40. What is Calibration? “t he operation which assure that an instrument readings are accurate with referenced to established standards. ” Laboratory instruments that need to be calibrated are balances, spectrophotometers, pH meters etc. Calibration is performed using primary reference standards. 40

41. Need for Calibration? With a new instrument. When a specified time period is elapsed. When a specified usage(operating hours)has alapsed . When an instrument has had a shock or vibration which potentially may have put it out of calibration. Sudden changes in weather. Whenever observations appear questionable . 41

42. Validation Vs. Calibration A calibration is a process that compares a known (the standard) against an unknown (test's device). During the calibration process, the offset between these two devices is quantified and the test's device is adjusted back into tolerance (if possible). A true calibration usually contains both “as found” and “as left” data. A validation is a detailed process of confirming that the instrument is installed correctly ,that it is operating effectively, and must test all three operational effectively , and that it is performing without errors. Because a validation must test all three of these operational parameters ,it is broken into 3 different tests: IQ,OQ,PQ . 42

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44. Design Qualification “ Design qualification (DQ) defines the functional and operational specifications of the instrument and details for the conscious decisions in the selections of the supplier.” Points to be consider for inclusion in a DQ:- Description of the analysis problem Description of the intended use of the equipment Description of the intended environment Preliminary selection of the functional and performance specifications(technical, environmental, safety). 44

45. Installation Qualification “ Installation qualification(IQ) establishes that the instrument is received as designed and specified, that it is properly installed in the selected environment, and that this environment is suitable for the operation and use of the instrument.” Stages: Equipment management group. Support groups. Plant engineering group . 45

46. Operational Qualification “Operational qualification(OQ) is the process of demonstrating that an instrument will function according to its operational specification in the selected environment. 46

47. Performance Q ualification “ performance qualification(PQ) is the process of demonstrating that an instrument consistently performs according to a specification appropriate for its routine use.” 47

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50. Expectations of the customers General requirements may be stated as follows:- Size of the equipment Speed of the equipment Effectiveness of equipment ex: mixers Availability of spares, change parts, prompt services at reasonable cost Ease of operations, cleaning& workmanship Low dust & sound generation Lesser breakdowns Materials of construction Auto control systems Easy change overs overall good construction and workmanship Etc A) User requirement specifications: 50

51. B) preparation of D.Q and its certification If standard equipment's are being buyed then there is no need of D.Q, as we are accepting manufacturing design. If particular equipment is to be fabricated then User requirements should be considered when deciding on the specific design of a system or equipment. Approved vendor should be selected( a suitable supplier should be selected for appropriate system or equipment If the user for a specialized type of instrument ,then he must submit his requirements in the form of a detailed D.Q document to the supplier. Factory Acceptance Test(FAT) is performed at the manufacturer's premises before dispatch of the equipment to the purchaser . 51

52. C) Installation Qualification Equipment can be installed when it is qualified for installation i.e. when it passes the I.Q test. All the key aspects adhere to manufacturers recommendation appropriate codes& approved D.Q. Verifies that the correct equipment has been received & installed as per plan & protocol. Also that it is complete & undamaged (parts, services, controls, gauges & other components). Verifies that equipment has been properly installed and calibrated including connections to utilities. Document Records include: The supplier and manufacturer System or equipment name Model and serial number Date of installation 52

53. D) Operational Qualification Systems & Equipment's should operate correctly –operations verified as in the qualification protocol. verifies that the equipment operates consistently within established limits & tolerance over the defined operating ranges. Challenges equipment functionally to verify compliance with manufacturer's specifications & end user defined requirements. Documented Records: Training of operators provided training records system and equipment released for routine use after completion of operational qualification ,provided that All Calibration, cleaning, maintenance, training and related tests and results were found to be acceptable. 53

54. E) Performance Qualification Verifies that the equipment performs according to design specifications & user defined requirements in a reliable & reproducible manner under normal production conditions. Verified accordance with a P.Q protocol. Documented Records: Performance qualification report shows satisfactory performance over a period of time, carried out long to prove that the equipment is under control and turns out product of specified quality consistently. 54

55. Assembling of a Validation Protocol Equipment validation is designed in the form of certain documented formats or protocols. Helps in systematizing the study of equipment. Different formats have been specified for designing protocols and carrying out I.Q,O.Q& P.Q. 55

56. Purpose: This procedure details the assembly & contents of a validation protocol for use in validation testing. Principle: Validation protocol is generated by a Validation Specialist/Engineer. Protocol sections contain required procedures & forms. Procedure describe “how” the system is to be validated, while the forms document these procedures & provide a written record of the executed qualification & validation protocol. 56

57. Testing procedure: Protocol package is divided into I.Q O.Q P.Q Sections of a standardized protocol: Table of contents List of standard sections Unique testing procedures approval page . Preapproval section Final approval section Description statement of purpose standard operating procedures Correct, Complete & most Current Versions Calibration Utilities 57

58. Testing Procedures: Installation Qualification Inspection checklist Installation checklist Environmental Requirement Operation Qualification Alarm Testing Unit Operation System Capacity Environmental Requirement Additional testing Performance Qualification Training Acceptance criteria Deficiency & Corrective Action Data summary Appendix 58

59. Installation Qualification- Equipment or System Purpose: The objective of this procedure is to describe testing sections of an I.Q for piece of equipment or system. Principle: It includes the section of standardized protocol. “Assembling a Validation Protocol”. A general description of the approach & rationale to be used when writing the Installation & Inspection sections of the protocol. Procedure: a)Inspection Checklist. b)Installation Checklist. 59

60. a) Inspection Checklist: An “Instruction” sheet explains how this section is physically executed . This facts are documented in the appropriate space on the form. Any deviations are noted on that pag e & also in the Deficiencies & Deviations section of the protocol. Instruction Explains how this section is physically executed Table of contents Lists all the major components of equipment Specified Manufacturer's specification Actual The thing which is actually observed is recorded 60

61. Two approaches are commonly employed 1) Like Components 2) Order of Sequence Like components of the system may be grouped in Table of Contents but their individual characteristics will be listed out separately. Example: table of contents. separately Valves. Types of valves Alarms and interlocks. Alarms Order of Sequence starts with the component which begins the process and proceeds through the system. Example : P &ID drawing ( piping and installation diagrams ). 61

62. b) Installation Checklist: This section of the protocol determines whether or not a piece of equipment or system as a whole meets the manufacturer's design specifications. Its is recorded as “yes” or “no” The person performing the physical validation will initiate & date each statement. All “No” responses will be recorded in the Deficiencies & Deviations of the protocol. Environmental Requirement: Specifically addresses temp ,humidity etc. Of a particular equipment. It may be added to the inspection checklist of each component and used only if applicable . 62

63. Operation Qualification-Equipment or system Purpose: To define the procedure for the Operation Qualification of a piece of equipment or system. Principle : After I.Q, a Verification Of equipment or system capability is performed. Includes but not limited- alarm testing, control system testing, operation & maintenance procedures. Test Equipment: List the necessary instrument to conduct the test procedure & verify that all instrumentation is calibrated & remain calibrated. 63

64. Test Procedure: The O.Q protocol include standardized section listed in “Assembling a Validation Protocol”. Individual protocol “Testing Procedures” which will include a) Alarm Testing: specified alarm signal or alarm reaction occurs as designated. The alarms to be tests are listed, expected results are recorded & Acceptability determined. Any deviations or comments are also reported. b) Operation Testing: operates is designed ,testing may involve stimulated runs using components will be used with the marketed pdt information from the vendors will help in determining which tests to be performed, along with this tests results whether acceptable or not need to be documented. Any deviation or comments also reported. Additional Testing Environmental Requirement Preventive Maintenance 64

65. Process/Product/Performance Qualification/ Validation Purpose : To define testing requirements in a P.Q protocol. Principle: This gives a general outline Of the issues to be considered in a P.V testing plan. Includes: - background and reason for the plan -testing method used -predetermined general / specific acceptance criteria Test Equipment: List any test instruments necessary to conduct this validation & verify that all instrumentation is calibrated prior to functional testing & remains calibrated for the test duration. 65

66. Procedure : It is “final ” phase of the validation process. Before PQ validation testing is implemented for all processes, product specifications are established & judged acceptable. This testing will validate the effectiveness & reproducibility of process or product. Some of the protocol“ Testing Procedures” should be considered. Testing Procedures( Design of Experiment). Worst Case conditions. Microbiological Challenges 66

67. Testing Procedure(Design of Experiment): Essential component. These procedures are tailored to challenge the exact process or product to be validated using the normal operating parameters in SOP. Validation will demonstrate that by using these parameters the quality product intended can be produced consistently. Worst Case Conditions: Unique Not necessarily that product or process failure must be induced. it encompass upper & / lower limits & circumstances(as stated in SOP). Will pose the greatest chances of process or product failure when compared to actual production conditions. 67

68. Microbiological Challenges: Controlled environment is necessary for the production of many pharmaceutical pdts & sterile envt is essential for the mfg. of Parenteral. Depending on circumstances, all or one of the following challenges may be implemented: -biological microorganism profile. -biological spores. -biological endotoxins. -media fills. Testing for microbial growth is performed under certain challenge conditions & for a predetermined length of time (days, weeks, months). The objective is to prove sterility as defined by compendia tests. It also requires a monitoring program to prove reproducibility. 68

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71. Validation of autoclave 71

72. Definition: An autoclave is a pressure chamber used to carry out industrial processes requiring elevated temperature and pressure different to ambient air pressure. Autoclave are used in medical application to perform sterilization. Sterilization of media, Glass wares, Gloves, Gowns Etc. It is a moist type of sterilization unit. Normal Temperature & Pressure for Autoclave is 121 °C & 15lbs pressure. 72

73. Sterilization can be defined as any process that effectively kills or eliminates transmissible agents (such as fungi, bacteria, viruses) from surface, equipment, foods, medications or biological culture medium. sterility assurance level (SAL) of 10 means that there is less than or equal to one chance in million that particular item is contaminated or unsterile following sterilization process. Autoclave was invented by Charles c hamberland in 1879.The name comes from G reek auto- self, and L atin clavis - key, a self- locking device. 73

74. How an autoclave works: Steam does enters the chamber jacket, passes through an operating valve & enters the rear of the chamber behind a baffle plate. It flows forward & down through the chamber & load exiting at the front bottom. A pressure regulator maintains chamber & jacket at a minimum of 15lbs, the pressure required for steam to reach 121 °C (250°F). Overprotection is provided by steam valve. 74

75. Need and Importance: 1. The proper sterilization of medical devices, surgical instruments, supplies and equipment utilized in direct patient care and surgery is a critical aspect of the modern health care delivery system and directly impacts patient safety. 2. Sterilization is very important in the medical industry. Without sterilization, infections would fly around and thousands of lives would be lost. Sterilization helps to prevent the development and spread of infection. 3. In the pharmaceutical industry it used for surgical dressings, sheets, surgical and diagnostic equipment, containers, closures, aqueous injections, ophthalmic preparations and irrigation fluids etc. 4. It is generally accepted that sterility assurance level (SAL) of type equation here is appropriate for items intended to come into contact with compromised tissue, which has lost the integrity of natural body barriers.   75

76. Basic Qualification approach: User requirement specification (URS) User or customer of equipment has certain expectation about the equipment which wants to use. These expectations are generally in the form of his requirements. It is called as user requirement specifications. Design qualification (DQ) Design qualification may verify that design of equipment, system/facility is according to requirement of user and current good manufacturing practices. Installation qualification (IQ) Installation qualification is conducted to prove that equipment/system has been installed as per user and manufacturer recommendation and verifying that all required utilities have provided safe operation of equipment/system. · Utilities specification · Drawing specification (electrical, mechanical) · Construction material in product contact · Operating and maintenance manual 76

77. Operational qualification (OQ) The operational qualification process is intended to demonstrate that the components are operating properly and ready for performance or load testing. Operational qualification shall be done “without load”. Performance qualification (PQ) Performance qualification is documented evidence to prove that equipment/system is performing under specified condition. It involve in taking trial under “loaded condition. 77

78. D value: Refers to Decimal Refraction Time. The time required at a certain temperature to kill 90% of the organisms being studied. Thus after an organism is reduced by 1 D. Only 10 % organism is remained. Ex:- D value of 1.5 = 1CFU D value is affected by type of microorganism used as BI. Formulation components & characteristics. Surface on which org is exposed. Temperature, gas concentration ,radiation dose. D value found by 2 methods:- a) Survivor curve method. b) Fraction D method. 78

79. Z value: Refers to temperature change required to produce a 1 log reduction in D value. it is a reciprocal of slope of plot of log D vs T at which D value is found i.e., increase in temperature required to reduce D value of organism by 90%(1 log reduction). F value: The number of minutes to kill a specified number of microbes with a Z value of 10 °C at a temp of 121°C. Measures Equivalent time . 79

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82. IQ: Installation tests should check . Electrical supply. Temperature & Humidity. Interference of other equipment. Accuracy of BI is certified to National standards. Temp & pressure is maintained within specifications during sterilization cycle. The leakage into the chamber during a vaccum cycle does not exceed the specified maximum. water & steam quality comply with sterilization specification. mechanical equipment specification. control & instrumentation specifications. site specifications /utilities. Approval documentation. control system documentation. 82

83. OQ: Operation tests should check: Temp & pressure display test Vacuum test Calibration of thermocouples Heat distribution test PQ: Heat penetration test Microbial challenge test Microbial limit test Other test involves a. Bowie -dick test 83

84. Vacuum leak test: Objective : To verify the leakage in sterilization chamber during vacuum hold time when the sterilizing chamber is empty. Principle : These tests are designed to show that the sterilizer chamber does not leak in empty chamber. Leakage of air into the chamber is not acceptable for two reasons: The presence of air inhibits penetration of the load by the sterliant (Steam) and prevents sterilization. 2. Air leaking into the chamber during the sterilization and drying cycle are not passed through the bacteria retentive filter, and therefore there is a risk of contamination of the load The test is performed by measuring the change in vacuum in the chamber when all the valves leading to it have been closed and the vacuum source is isolated. 84

85. Procedure: Ensure that the chamber temperature is stable at ambient and compressed air is on with high pressure and ensure that gasket lubrication is proper and switch provided on panel board. Start the vacuum leak rate test cycle and observe the pressure in the pressure gauge of steam sterilizer and Cycle allow the pressure to drop down. Machine will close all the valves connected to the chamber and stop the vacuum pump and note the time and pressure (P1). Wait for stabilization period of 5 minute (±10 second) and note down the pressure again (P2) and Wait for another 10 minute (± 10 second) and note down the pressure third time (P3). Return to atmospheric pressure and continue to run for next cycle where vacuum leak rate should not be more than acceptance criteria. Acceptance criteria: Vacuum leak rate should be NMT 0.013 bar / 10min 85

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87. Bowie-Dick test: Objective : To ensure that the vacuum pulses applied before the sterilization hold period are sufficient to remove the entrapped air or non-condensable gases so as to facilitate the event and rapid steam penetration into all parts of load and maintaining this condition during sterilization holding time. Principle : Sterilization is achieved by the rapid and even penetration of steam into all parts of the load and the maintenance of these conditions for the specified holding time. To ensure this, it is essential to remove air from the chamber and load, and to provide a steam supply which contains a minimal volume of Non-condensable gases .The Bowie Dick test shows whether or not steam penetration is taking place by testing the presence of Non condensable gases in the chamber, but it does not confirm that the sterilization condition in the load is achieved or not 87

88. Procedure: Place the Bowie Dick test paper on the bottom shelf of the sterilizer just above drain point (100mm over the drain) Air removal study shall be performed in empty chamber by placing the Bowie Dick test paper. it consist of standard paper pack and indicator sheet Start the cycle by pressing enter key After the cycle is over open the door from control area side and take the sterilized test paper from the autoclave and check the indicator paper for uniform color change As Bowie Dick test paper is designed to simulate the garment pack, it used to test the efficiency of the air removal from the steam sterilizer Three cycle of air removal study shall be performed (initially) by using fresh indicator paper This test shall be performed by using Bowie Dick test cycle. To fulfil the maximum exposure requirement, the sterilization cycle shall have 17 minutes at 121°C to 123°C sterilization period. 88

89. Set Parameters : 17 minutes cycle at a temperature of 121°C Place of keeping Bowie -Dick Indicator : Place the Bowie dick indicator approximately 100 mm to 200 mm above the sterilization chamber base. Acceptance criteria : The Bowie dick indicator should show uniform color change (Yellow to Brown / black) after the cycle. No change or no uniform change or air entrapment (bubbles) spot on the test sheet indicates inadequate air removal from the sterilization base chamber. Frequency: Run the test for 3 consecutive cycles at the time of Initial Qualification. 89

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92. Heat distribution study (empty chamber): Objective : To verify the temperature uniformity throughout the chamber and to locate the cold spot in Empty Chamber. The sterilizer is capable attaining a temperature of 121° C throughout the sterilizing hold period in Empty Chamber . Procedure : Insert 16 no of temperature sensors inside the chamber through the validation port of sterilizer. Seal the port with silicon sealant to ensure that no steam leakage during operations of sterilizer. Fix all the probe at different location in the sterilizer so that sensors do not touch the metallic surface of the chamber. Connect the temperature sensors to the data logger, which can scan and print the actual temperature and pressure at different locations. After completion of sterilization cycle check the thermograph in the data logger for attaining set temperature and pressure during the sterilizing hold period. If any deviation observed repeat the cycle after taking necessary correction . Acceptance criteria: Temperature distribution within the chamber must be between 121°C to 123°C at all location during the sterilization period (dwell time). There should not be any slowest heating point (cold spot) in the autoclave chamber and equilibriumtime should not be more than 30 second. 92

93. Heat distribution study (loaded chamber) Objective : To verify the temperature uniformity throughout the chamber and to locate the cold spot in loaded Chamber. The sterilizer is capable attaining a temperature of 121°C throughout the sterilizing hold period in loaded Chamber . Procedure: Insert 16 no of temperature sensors inside the chamber through the validation port of sterilizer. Seal the port with silicon sealant to ensure that no steam leakage during operations of sterilizer. Fix all the probe at different location in the sterilizer so that sensors do not touch the metallic surface of the chamber. Load the article as per loading pattern in the autoclave chamber. Loaded chamber heat distribution study shall be performed separately for all loading patterns. One cycle shall be performed for each loading type for loaded chamber heat distribution study Connect the temperature sensors to the data logger, which can scan and print the actual temperature and pressure at different locations. After completion of sterilization cycle check the thermograph in the data logger for attaining set temperature and pressure during the sterilizing hold period. If any deviation observed repeat the cycle after taking necessary correction . Acceptance criteria: Temperature distribution within the chamber must be between 121°C to 123°C at all location during the sterilization period (dwell time) There should not be any slowest heating point (cold spot) in the autoclave chamber and equilibrium time should not be more than 30 second . 93

94. Heat penetration study Objective: In order to verify sterilizing temperature has been reached in each load subjected to moist heat sterilization, it is necessary to conduct heat penetration studies. This study is conducted to ensure that the coolest unit within a pre-defined loading pattern (including minimum and maximum loads) will consistently be exposed to sufficient heat lethality (minimum "F0"). Procedure: Insert 16 no of temperature sensors inside the chamber through the validation port of sterilizer. Seal the port with silicon sealant to ensure that no steam leakage during operations of sterilizer. Fix all the probe at different location in the sterilizer so that sensors do not touch the metallic surface of the chamber. Load the article as per loading pattern in the autoclave chamber. Loaded chamber heat distribution study shall be performed separately for all loading patterns. Arrange the load as specified keep at least 15 biological indicators and 10 thermo chemical indicators shall be used for each cycle. Load placed at the identified cold points must have indicator and temperature sensor in all three runs. One biological indicator and thermo chemical indicator along with external temperature sensor shall be placed at drain point in all three cycle. Perform the sterilization by operating the program specified for each load type as per standard operating procedure and start the data logger and steam sterilizer simultaneously. After the sterilization cycle is completed, stop data logger and open the sterilizer and take out the biological indicator and thermo chemical indicator from load and send to microbiological lab for testing. The biological indicator shall aseptically inoculate into sterile soybean casein digest media (SCDM) and incubated at 55 – 60 oC and liquid load at 35 - 39oC for 7 days and check the thermo 94

95. chemical indicator for the compliance as per manufacturer recommendation for color change (i.e. Brown).Take out temperature chart/data logger and inbuilt temperature recorder, report of biological indicator. Check against acceptance criteria for compliance and determine the F o value and compare against acceptance criteria. Take out external temperature sensor from the chamber and perform vacuum leak rate test. Acceptance criteria Temperature distribution within the chamber must be between 121°C to 123°C at all location during the sterilization period (dwell time) Sterilization temperature should be maintained for NLT 15 minute for minimum 10 thermo couple during hold time. Biological indicator ( Geobacillus s tearothermophillus ) should show complete sterilization(i.e. no growth after incubation. 95

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98. References : 1. Manohar A. Potdar “Pharmaceutical Quality Assurance” , Nirali Publication Page no 8.13-8.20. 2. Nash Robert “Pharmaceutical Process Validation” Marcel Dekker Inc. Equipment's and validation page no 443. 3. Encyclopedia of pharmaceutical technology volume 1 by James. 4. The theory & practical of industrial pharmacy by Leon Lachmann page no 625 98