VALIDATION AND CALIBRATION OF PHARMACEUTICAL EQUIPMENTS.pptx

VALIDATION, CALIBRATION AND ICH GUIDELINES

1. VALIDATION 1 SUBJECT: MODERN PHARMACEUTICS FACULTY-IN-CHARGE: Dr. PRASANTH MS ASSOCIATE PROFESSOR, DEPARTMENT OF PHARMACEUTICS PRESENTED BY: LANIYA NASRIN K 1 ST SEMESTER M PHARM, DEPARTMENT OF PHARMACEUTICS GOVERNMENT MEDICAL COLLEGE,THIRUVANANTHAPURAM

2. 2 CONTENTS

3. 01 PHARMACEUTICAL VALIDATION 3

4. 4 DEFINITIONS FOR PHARMACEUTICAL VALIDATION

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6. 6 Releasing a poor quality product , Recalls. Delay in approval of new drugs Quality problems confounding clinical trial data Low process capability NEED OF VALIDATION T o minimize these problems we need to do VALIDATION It assures the product quality as per customer requirements.

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8. 8 SCOPE OF VALIDATION It is a vast area of work and it practically covers every aspects of pharmaceutical processing activities, hence defining the scope of validation become really a difficult task.

9. 9 It requires an appropriate and sufficient infrastructures including: Organization, documentation, personnel and finances . Involvement of management and quality assurance personnel Personnel with appropriate qualifications and experience. Extensive preparation and planning before validation is performed. Validation is done in a structured way according to documentation including procedures and protocols. Validation should be performed for: New premises, equipment, utilities and systems New processes and procedures, at periodic intervals W hen major changes have been made.

10. 10 Validation in accordance with written protocols. A written report on the outcome to be produced. Validation over a period of time At least three consecutive batches (full production scale) to demonstrate consistency. Process, materials and equipment must prove consistent yield of the product for the required quality. Significant changes (facilities, equipment, processes) – should be validated. Manufacturer’s to identify what validation work is needed Risk assessment approach used to determine the scope and extent of validation needed

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13. 13 1.REDUCTION OF QUALITY COSTS   Quality costs for a pharmaceutical industry is about 10-15% of manufacturing costs. A. Preventive costs: Costs in order to prevent quality failure, Quality planning, Training, Documentation, SOPs, Monographs, Preventive maintenance, Calibration, Sanitation, Process validation, Quality assurance auditing, Annual review of data. B. Appraisal costs:    Inspection and testing costs of raw materials, packaging material, in process materials, finished products and stability testing.

14. 14   C. Internal failure costs : Cost of rejections, reworks, re-inspection, retests, wastage, sorting substandard materials.  D. External failure costs : After the product has left company’s ownership Recalls Complaints Returns due to quality related problems

15. 15 2. PROCESS OPTIMIZATION Make the process as effective, efficient, perfect or useful as possible at the minimum cost. Trained and qualified personals are the key element of improving efficiency and productivity. Advantages of process optimization: Fast and more accurate analytical techniques Development of standards Reduced energy costs Optimum batch sizes

16. 16 TYPES OF VALIDATION

17. DOCUMENTATION OF VALIDATION AND CALIBRATION The validation and calibration activity cannot be completed without proper documentation of each and every minute activity with all details. Documentation of validation and calibration includes: VALIDATION MASTER PLAN(VMP) VALIDATION PROTOCOL(VP) VALIDATION REPORTS(VR) STANDARD OPERATING PROCEDURE(SOP) CALIBRATION MASTER PLAN(CMP) CALIBRATION CERTIFICATE(CP) 17

18. 02 VALIDATION MASTER PLAN (VMP) 18

19. 19 VALIDATION MASTER PLAN (VMP) VMP is a comprehensive document describing the applicable validation requirement for the facility, and providing a plan for the meeting those requirements It is a documented evidence that provides a high degree of assurance that a specific process will consistently produce a product that meets its pre-determined specifications and quality attributes.

20. 20 A VMP is the foundation for the validation program and should include process validation, facility and utility qualification and validation, equipment qualification, cleaning and computer validation FDA inspectors often looks at VMP during audit to see whether facility's validation strategy is well organized or not

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23. 23 ORGANISATION OF VMP VALIDATION BASIC RISK ANALYSIS VMP DETAILED RISK ANALYSIS QUALIFICATION VALIDATION OF COMPUTERISED SYSTEM VALIDATION DESIGN QUALIFICATION(DQ) INSTALLATION QUALIFICATION(IQ) OPERATIONAL QUALIFICATION(OQ) PERFORMANCE QUALIFICATION(PQ ) PROCESS VALIDATION CLEANING VALIDATION ANALYTICAL METHOD VALIDATION

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26. 26 1. INTRODUCTION 2. METHODOLOGY The introduction of VMP should include the following details: A description of facility, its premises and equipment and its purpose intension and Scope of validation Other relevant site policies and plans like factory or corporate policy statement on GMP/QA This section should address the pre-determined requirements by identifying the standards that are to be applied to the facility These are then used in the development of the acceptance criteria that are used to judge the validation It also involves planning and execution of documents such as protocols, records, report, or others The standard will involve 3 elements: Regulatory and guidance documents National standards Company Standards

27. 27 3. QUALIFICATION Action of proving and documenting that the equipment and ancillary system are properly installed, work correctly and actually lead to the expected results. This section mainly includes all aspects of the design, procurement, installation and commissioning process. Providing documents evidence that the design of the facility and equipment meet the requirement of the user specification and GMP.

28. 28 1 DESIGN QUALIFICATION(DQ) Design specification to ensure that all specified design element have been included and that the design meets the relevant regulatory and statutory requirements 2 INSTALLATION QUALIFICATION(IQ) Verifies that The equipments/system/process is installed correctly Supplied as specified Integrated into the site calibration, maintenance system and available for use 3 OPERATIONAL QUALIFICATION(OQ) Verifies that The equipments/system/process is operating correctly Complies with functionality requirements Integrated into the system and QMS. 4 PERFORMANCE QUALIFICATION(PQ) Verifies that The equipments/system/process is continuously meeting performance criteria for routine use Performing adequately for routine use in commercial production.

29. 29 VMP includes the incorporations of information into formal written protocols , which serves as guidance for executing the appropriate validation activities. Protocols should be developed for DQ,IQ,OQ & PQ. INFORMATION INCLUDED IN SPECIFIC PROTOCOLS ARE: Description of the system Qualification objectives Scope Responsibilities and data collection procedures Test procedures, specific acceptance criteria Documentation procedures Summary and deviation reports

30. 30 DESIGN QUALIFICATION INSTALLATION QUALIFICATION Design of premises and equipments are influenced by user’s requirements Prepare user requirement document (URD) It must include: Basis of design Process flow diagram Process and instrumentation diagram Purpose of equipment Design requirement Environmental condition Facilities for control, regulation and measurement I Q protocols includes Verification of calibration of critical installed components Verification of procedures Verification of major components Verification of control and monitoring devices Reference manuals

31. 31 OPERATIONAL QUALIFICATION(OQ) PERFORMANCE QUALIFICATION(PQ) OQ protocols includes: Verification of test equipment calibration Verification of controls and indicators Verification of major components of operation Verification of alarms Computer control system testing Power failure/recovery testing Functionality testing of distribution system PQ protocols includes: System sampling Equipment-start test System invasive test Equipment robustness test Appropriate data /results

32. 32 VALIDATION MASTER PLAN (VMP) USER REQUIREMENT SPECIFICATION (URS) FUNCTIONAL REQUIREMENT SPECIFICATION (FRS) TECHNICAL REQUIREMENT SPECIFICATION(TRS) CONSTRUCTION FACTORY ACCEPTANCE TEST(FAT) SITE ACCEPTANCE TEST(SAT) INSTALLATION QUALIFICATION(IQ) OPERATION QUALIFICATION (OQ) PERFORMANCE QUALIFICATION (PQ) MAINTAINING STATE OF VALIDATION V-MODEL

33. 33 4.PERSONNEL 5.SCHEDULE The CFR 21 s tates that “each person engaged in and each person responsible for supervising the manufacture, processing, packaging or holding a drug product shall have the education, training and experience to enable that person to perform the assigned function” VMP must address the aspects like: experience of personnel, in-house training reports Documenting the training is essential and is a requisite of the GMP The work program is essential and should be prepared at an early stage A good plan will contain all the necessary features which are to be considered during execution of a plan and determine the control of the project It ensures that all the personnel involved in the VMP are not only aware of the engineering targets, but also the validation targets

34. 34 6.PREVENTIVE MAINTENANCE This is the responsibility of site maintenance operation department This activity should be performed during the design phase, and the documentation required should be included in the requisition 7.PROCEDURE These covers engineering standards used in the project design, through to commissioning phase, and the facilities standard procedures SOPs

35. 35 8.CHANGE CONTROL This section of VMP should lay down requirements for a set of procedure change control that cover: The project through design, construction and commissioning The ongoing change that will inevitably occur in both the process and the equipment and Engineering aspects

36. 36 9.DOCUMENTATION 10.APPENDICES This section usually used to identify the documentation that should be produced for processing like: Engineering drawing Equipment supplier drawing documents Factory acceptance document IQ documents OQ documents PQ documents The appendices is mostly used in VMP to hold the information of type of document and formats that will be used in the execution stage

37. 37 Template

38. 03 CALIBRATION MASTER PLAN (CMP) 38

39. 39 CALIBRATION The process of comparing the response of same instrument or system to a standard instrument or system over some measurement range Calibration is a necessary component to ensure the authenticity of qualification and validation

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41. 41 CALIBRATION MASTER PLAN(CMP) A written document that describes the company's policy for calibration of the equipment and instruments It is a leading document in defining the requirement necessary for establishing and implementing an effective calibration control Programs

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43. 43 CALIBRATION PLAN PLANNING AND SCHEDULING ASSIGNING EXECUTION VALIDATION REPORTING MAINTANANCE STRATEGY TARGET SCOPE sender Maintenance Responsible QA INPUT: calibration work order OUTPUT: calibration certificate Maintenance Responsible QA receiver Ensure quality and sustainability on instrumentation Clear and consistent management of calibration

44. 44 Calibration process must be managed and executed in a professional manner A particular place for all calibration operations to take place and keeping all instruments for calibration . A separate room is preferred for: better environmental control better protection against unauthorized handling of the calibration instruments. Calibration procedures, used for quality control functions, are controlled by the international standard ISO 9000 . It requires that all persons using calibration equipment be adequately trained. A.CALIBRATION PROCESS

45. 45 A.1-MASTER INSTRUMENT LIST A.2-EQUIPMENT CLASSIFICATION 1.Serial number 2.Name of instrument 3.Location 4.Accuracy required 5. Range of measurement 6.Due date of next calibration 7.calibration certificate and number CRITICAL EQUIPMENT NON-CRITICAL EQUIPMENT Direct measurement that affect final product quality Indirect measurement that will not directly affect the final product quality A.3-VERIFICATION Applicable to equipment that cannot be calibrated verification against measurement standard with correction factor documented Actual reporting of result shall include the correction factor Temperature correction factor- 2  

46. 46 A.4-OUT OF CALIBRATION Remove equipment from use To determine source of inaccuracy All investigation findings should be documented. A.5 CALIBRATION CERTIFICATE It includes: Name and address of contracted calibration laboratory Name and address of client Description and identification of item calibrated Environment condition when calibration was done Date of receipt of instrument, date of next calibration Calibration method Result of calibration Signature and title of person responsible for calibration A.6-TIME INTERVAL OF CALIBRATION Depending on : classification of critical/non-critical Usage (light/heavy usage) Handling Manufacture's recommendation

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48. 48 A.7 RECORDS OF CALIBRATION Records will be maintained for all the calibrations done It should be according to the GMP The Individual calibration history files will be prepared and maintained for each instrument The records will be maintained and stored in the metrology A.8-LABELLING All calibrated equipments are labelled to indicate its status Following declaration are to be made after calibration "calibrated“ or "calibration required“ Label should contain: Date of last calibration Date of re-calibration person responsible for calibration calibration certificate number

49. 49 PROCEDURE FOR CMP

50. 04 ICH AND WHO GUIDELINES FOR CALIBRATION AND VALIDATION OF EQUIPMENTS 50

51. 51 EQUIPMENT VALIDATION Equipment is a physical entity which is used to carry out a general or specific activity in the plant Equipment may be single piece or set of integrated piece to perform common activity SINGLE PIECE: Tablet compression machine, HPC, FTIR, Weighing balance INTEGRATED PIECE: Water demineralizing plant, Air handling system Equipment validation -As per FDA, “Action of proving that any equipment works correctly and leads to the expected result in equipment validation”. It is not a single step activity but instead result from many discrete activities .

52. 52 ICH AND WHO GUIDELINES FOR CALIBRATION OF EQUIPMENT Calibration of an instrument is the process of determining it’s accuracy The process involves obtaining a reading from the instrument and measuring its variation from the reading obtained from a standard instrument Calibration adjust precision and accuracy of instrument Calibration achieves 2 main objectives : Accuracy & Traceability

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57. 57 ICH AND WHO GUIDELINES FOR VALIDATION OF EQUIPMENT

58. 58 ICH GUIDELINES FOR VALIDATION OF EQUIPMENT ICH Q2 guidelines are followed for validation of equipment which define the objective of validation of an analytical procedure to demonstrate that it is suitable for its intended purpose It should follow various parameters and requirements as follows

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60. 60 1.ACCURACY The accuracy of an analytical procedures expresses the closeness of agreement b/w the value which is accepted either as a conventional true value /an accepted reference value This is termed Trueness Accuracy should be established across the specified range of the analytical procedure Assessed using a minimum of 3 concentration levels , each in implicate

61. 61 2.PRECISION The precision of an analytical procedure expresses the closeness of agreement b/w a series of measurements obtained from multiple Sampling of the same homogeneous sample under the prescribed conditions Precision considered at 3 levels: REPEATABILITY INTERMEDIATE PRECISION REPRODUCIBILITY

62. 62 2.A-REPEATABILITY Express the precision under the same operating conditions such as same measurements/same procedure/same equipment over a short interval of time Referred as Intra-assay precision should be assessed using of 9 determinations/ minimum of 6 determinations at the 100% level 2.B-REPRODUCIBILITY Expresses the precision between the laboratories or inter-laboratory trials It is beneficial when an analytical method is standardized or is going to be used in more than one laboratory It is not always needed for single lab validation

63. 63 2.C-INTERMEDIATE PRECISION It expresses with in laboratories Variations: The precision obtained in a single laboratory over a longer period of time and takes Into account more changes that repeatability Different days, different analysts different equipment These factors are constant with in a day but are not constant over a longer time period and thus behaved as random

64. 64 3.LIMIT OF DETECTION(LOD) The detection limit of an individual analytical procedures is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.

65. 65 4.LIMIT OF QUANTITATION(LOQ) The quantitation Limit of an individual analytical procedure is the lowest amount of analyte in a Sample which can be quantitatively determined For the determination of Impurities and or degradation

66. 66 5.LINEARITY 6 .ROBUSTNESS The linearity of an analytical procedure is its ability to obtain test results which are directly proportional to the concentration of analyte in the sample Robustness is a measure of its capacity to remain unaffected by small, but deliberated in method parameters and provides an indication of its reliability during normal usage Change in of mobile phase Change in column Change in temperature Flow rate

67. 67 7.RANGE 8.SNR (SIGNAL TO NOISE RATIO) The range of analytical procedures is the interval between the upper and lower concentration of analyte in the sample Acceptance range having linearity, accuracy and precision FOR DRUG SUBSTANCE AND DRUG PRODUCT ASSAY 80-120% OF TEST CONCENTRATION FOR CONTENT UNIFORMITY ASSAY 70-130% OF TEST CONCENTRATION FOR DISSOLUTION TEST METHOD 20% OVER ENTIRE SPECIFICATION RANGE It is a power ratio between a signal and background noise SNR SNR  

68. 68 9.SPECIFICITY Ability of an analytical methods to measure the analyte free from interference due to other components(impurities, degradants, matrix…)

69. 69 10.RUGGEDNESS 11.TRANSFERABILITY 12.SENSITIVITY 13.SST(SYSTEM SUITABILITY TEST) The ability of the method to be used correctly by others with out seeking additional information Smallest quantity that can be detected accurately measured Check the theoretical plates, tailing factor, resolution and % RSD Result should be within specification limit It is established by 2 different system , column and analyst Repeatability will be checked by minimum of 5 different concentration prepared separately from homogeneous sample %RSD of assay results of analyst – should be more than 2%

70. 05 Validation in pharmaceutical industry, PP Sharma, 2 nd edition,pageno:107-123 Pharmaceutical process validation, Robert A Bash and Alfred H Wachter, drugs and the pharmaceutical sciences, 3 rd edition, page no:15 Validation of analytical procedures: text and methodology Q2(R1) ICH harmonized tripartite guideline, www.database.ich.org ICH guideline Q2(R2) on validation, www.ema.Europa.eu Process of validation in pharmaceutical industry- www.core.ac.uk Calibration master plan- www.flairpharma.com REFERENCES 70

71. 71 THANK YOU