Validation

M.pharm (Pharmaceutics) Modern Pharmaceutics unit- Validation Part-1 introduction, scope and merits of validation, Validation and calibration of Master plan, ICH & WHO guidelines for calibration and validation of equipment.

1. VALIDATION MEHAK AGGARWAL M.PHARM (PHARMACEUTICS)

2. CONTENT Introduction Objectives of Validation Scope & Merits of Validation Validation Master Plan Calibration Master Plan ICH and WHO guidelines for Calibration & Validation of equipment References 1/18/2022 Mehak Aggarwal 2

3. INTRODUCTION As per FDA Validation, It is defined as “ establishing a Documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes”. As per WHO, Validation means providing documented evidence that any procedure, process, activity or system actually leads to the expected results. According to European commission, validation is “Action providing in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or system actually lead to the expected results”. 1/18/2022 Mehak Aggarwal 3

4. OBJECTIVES To reach risk of regulatory non-compliance. Reduction of time to the market for the new products. Eliminates the scrap and reduces the defect cost. To reduce chances of product re-call from market. The final release of product batch would be expedited. It requires less in-process control and end process testing. Parametric release of batch can be achieved in validation. 1/18/2022 Mehak Aggarwal 4

5. SCOPE OF VALIDATION Pharmaceutical validation is a vast area of work and it practically courses every aspect of pharmaceutical processing activities, hence defining scope of validation becomes a really difficult task. However, a systematic look at the pharmaceutical operations will point out at least the following areas for pharmaceutical validation: Analytical Facilities Manufacturing operations Product design Cleaning 1/18/2022 Mehak Aggarwal 5

6. MERITS OF VALIDATION Knowledge of the process increases during the validation process. Consistency of the process is ensured. It decrease the risk of the manufacturing problems. Ensures the fluency of the production. Decrease the expenses. Decrease the risk of failing in GMP. 1/18/2022 Mehak Aggarwal 6

7. VALIDATION MASTER PLAN (VMP) A validation master plan(VMP) is a comprehensive document describing the applicable validation requirement for the facility, and providing a plan for the meeting those requirements. 1/18/2022 Mehak Aggarwal 7

8. Scope of VMP VMP includes all relevant expects relating to the production of pharmaceuticals in the production facility. The principle of v alidation, the organization of qualification and equipment are also described. A ll facilities used in various production areas, storage, services and the rooms for staff. In short, it is a documented evidence that provides a high degree of Assurance that a specific process will consistently produce a product that makes its predetermined specifications and quality attributes. 1/18/2022 Mehak Aggarwal 8

9. Why to perform VMP? VMP is not a requirement of FDA, but it has become almost an industry standard. It is important to include such a document, as it sets the overall goals and limits that will be followed during validation and can be referred to throughout the project. As a reference document, the plan permits the reviewer immediately to understand the scope of the validation and avoid misconceptions. T he validation plan is thus used to set the limits of validation, to define the scope of the project, the systems included and not included in the qualification and what the project will attempt to prove. 1/18/2022 Mehak Aggarwal 9

10. Members of VMP V alidation manager, QA department Member from production M ember engineering M ember from calibration lab M ember from QC lab M ember from maintenance M ember from HVAC department M ember from product development lab 1/18/2022 Mehak Aggarwal 10

11. Qualification Q ualification must be in accordance with the job requirement in combination with experience. The resumes of validation team members are presented in a separate folder, including contract help. 1/18/2022 Mehak Aggarwal 11 Content of VMP Introduction Introduction to validation process and facility. Includes- description of facility, premises, equipment, purpose, intension and scope of validation.

12. Methodology I t addresses pre-determined requirements by identifying standard that are to be applied to facility. T hese are then used in development of the acceptance criteria that are used to judge the validation. I t involves planning, execution of documents, reports, S tandards involve three elements- Regulatory and guidance document National standard C ompany standards 1/18/2022 Mehak Aggarwal 12

13. Qualification Th is section encompasses all aspects of design, installation and procurement, installation and commissioning process. Personnel VMP should lay down the qualification requirements. It must address the aspects like experience of personnel, in-house training reports etc. Documenting the training is essential and is a requisite of the GMPs. Schedule W ork program is essential and should be prepared at an early stage. A good plan will contain all necessary features which are to be considered during execution of a plan and determine control of project. It ensures that all personnel involved in VMP are not only aware of engineering targets but also validation targets. 1/18/2022 Mehak Aggarwal 13

14. Preventive maintenance I t is responsibility of site maintenance and operation department. T his activity should be performed during the design phas e and that documentation required should be, included in the requisition. Procedures These cover engineering standards used in project design, through to commissioning phases and the facilities standard procedures(SOPs). Change control Requirements for a set of procedures for change control that cover: project through design, construction and commissioning ongoing change that will inevitably occur in both process, equipment and engineering aspects. 1/18/2022 Mehak Aggarwal 14

15. Documentation Identify the documentation that should be produced for the processing like engineering drawing Equipment supplier drawing and documents factory acceptance documents IQ document OQ document PQ document  Appendices Appendix is mostly used VMP to hold information of type of documents and formats that will be used in execution stage. 1/18/2022 Mehak Aggarwal 15

16. CALIBRATION MASTER PLAN CALIBRATION T o maintain accuracy and precision of test equipment at all times. To ensure the highest level of confidence in all measurement that affect materials deposition decision with un broken chain of traceability to national standard. To determine whether equipment is still fit for its intended purpose. It is based on comparison of a primary standard or instrument of known accuracy with another equipment (to be calibrated). It is used to detect, report or eliminate by adjustment of any variation in the accuracy of equipment being calibrated. 1/18/2022 Mehak Aggarwal 16

17. CMP A ssigning responsibilities for equipment users, equipment managers, quality assurance personnel and calibration vendors to help and Shaw company-wide consistency and regulation of your processes. A pproving calibration vendors such that they are in compliance with the guidelines of your quality system. Identifying and labelling equipment. Processing investigations of out of tolerance conditions and other calibration related issues that may necessitate corrective action. Controlling and storing records, including calibration certificates, status change forms and calibration SOPs. 1/18/2022 Mehak Aggarwal 17

18. WHY CALIBRATE? C omponents age and equipment undergoes changes in temperature and humidity or sustains mechanical stress and therefore their performance degrades. T his is called drift. Then test results become unreliable. While drift cannot be eliminated, it can be detected and either corrected or compensated for through the process of calibration. Calibration: optimizes resources e nsures consistence ensure measurements 1/18/2022 Mehak Aggarwal 18

19. EQUIPMENT CLASSIFICATION Critical equipment Direct measurement that affect the final product quality specification. Non-critical equipment Indirect measurement that will not directly affect the final product quality. Shall be maintained based on company maintenance schedule. PROCESS OF CALIBRATION C alibration 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. Separate room is preferred because better environmental control better protection against unauthorized handling or use of calibration instruments. 1/18/2022 Mehak Aggarwal 19

20. P erformance of all calibration operations is assigned as the clear responsibility of just one person. C alibration procedures, used for QC function are controlled by International standard ISO 9000. It required that all persons using calibration equipment be adequately trained. VERIFICATION A pplicable to equipment that cannot be calibrated (adjustment, correlation, etc.). V erification against measurement standard with correlation factor documented. Actual reporting of result shall include the correlation factor- correlation factor = -2ºC measured value =24ºC reported value = 24ºC-2ºC=22ºC 1/18/2022 Mehak Aggarwal 20

21. CALIBRATION RECORDS CMP include the control of all critical measurement equipment that contain the following detail. Name I dentification by model number and serial number L ocation Owner/ responsible C alibration frequency C alibration due date C alibration certificate C alibration procedure 1/18/2022 Mehak Aggarwal 21

22. CALIBRATION CERTIFICATE N ame and address of contracted calibration laboratory. N ame and address of client. D escription and identification of item calibrated. E nvironment conditions when calibration was made. D ate of receipt of instrument, date of calibration and date of next calibration. C alibration method. R esult of calibration. S ignature and title of person responsible for the calibration. E xternal calibration contract shall be awarded to accredited by Nation Institution. 1/18/2022 Mehak Aggarwal 22

23. ICH AND WHO GUIDELINES FOR CALIBRATION & VALIDATION OF EQUIPMENT ICH GUIDELINES FOR CALIBRATION OF EQUIPMENT L ocal identification by a unique i dentification number and involvement in master GMP instrument list Procedure for instrument history file. A pproval by quality unit. Generation of procedure for verification and standardization of accuracy and reliability. F or approval of procedure, it must contain steps and forms required for calibration. Involvement of calibration stickers and auxiliary stickers program. P rocedure for tracking of Scheduled calibration activities. P rocedure for notifying users of calibration due dates, overdue calibrations and out of tolerance findings. 1/18/2022 Mehak Aggarwal 23

24. R eview of all systems, calibration records and procedure by quality unit. Involvement of procedure for reporting any GMP critical instrument. I nvolvement of calibration forms which are developed to record the calibration results. WHO GUIDELINES FOR CALIBRATION OF EQUIPMENT R egular calibration. E stablishment of specific procedure of calibration for every equipment. O nly authorized personnel should operate equipment. A vailability of up-to-date instructions for calibration verification results must be recorded on a control chart. Unique identification of each item of equipment for calibration. Keeping of records of each item of equipment to perform calibration. S ystematic verification of laboratory to prevent contamination. Establishment of maintenance procedure. 1/18/2022 Mehak Aggarwal 24

25. Out of service equipment. L abelling of equipment. V erification of equipment function and calibration status. EXAMPLE FOR CALIBRATION OF UV SPECTROPHOTOMETER Control of wavelength  Verify wavelength scale using absorption maxima of holmium per chlorate solution with the line of hydrogen or deuterium discharge lamp or lines of mercury vapor arc. The permitted tolerance is +/-1 nm for the range 200 to 400nm. Control of absorbance Check the absorbance using potassium dichromate solution UV at different wavelengths. 1/18/2022 Mehak Aggarwal 25

26. Limit of stray light Detected at a given wavelength with suitable filters or solutions; for ex. potassium chloride. Resolution power Record the spectrum of a 0.02% v/v solution of toluene in hexane UV. Ratio of the absorbance is NLT 1.5 . Spectral slit width Spectral slit width must be small compared with the half- width of the absorption band. 1/19/2022 Mehak Aggarwal 26

27. ICH GUIDELINES FOR VALIDATION OF EQUIPMENT 1 meter distance from walls and other obstacles. Easy to operate, clean and maintainable. Working should be at proper commissioned position. Certification of equipment. Checking of overhead heights. Proper source of light. Drop down utility sy stem. Design of equipment. Layout of equipment. Marking of pipelines as per their flow of direction. 1/19/2022 Mehak Aggarwal 27

28. Sop the equipment. Tracing of equipment. Identification marking for equipment. Cleaning of equipment. Distinguishing of the equipment. Record of each processing. WHO GUIDELINES FOR VALIDATION OF EQUIPMENT Equipment must be located, designed, constructed, adapted and maintained to suit the operation. Layout and design of equipment. Instalment of equipment. Production equipment. 1/19/2022 Mehak Aggarwal 28

29. Labelling of fixed pipe work. Cleaning of equipment. Labelling of equipment. Establishment of written procedures for each operation. Record keeping. EXAMPLE OF VALIDATION OF TABLET COMPRESSION MACHINE Execution of Design Qualification Execution of IQ, OQ and PQ Procedure Followed for Performance Qualification The blend/dummy material was unloaded into the hoppers on the both sides and the compression machine was operated at low speed (20RPM) as per operating instructions. Then the machine was set to run for 20 minutes continuously after adjusting the following parameters- 1/19/2022 Mehak Aggarwal 29

30. Individual tablet weight variation Weight of 20 tablets Hardness Thickness Disintegration time Friability Repeat the procedure at both medium (40RPM) and high speed (60RPM) with same set of parameters. Checking of parameters at different speeds. Report the results. Sampling Plan Collect 100 tablets for every 05 minutes. Compression parameters checked at different speeds. Optimum results obtained at 40 rpm speed. 1/19/2022 Mehak Aggarwal 30

31. REFERENCES Potdar MA, “cGMP, current good manufacturing practises for pharmaceuticals”, 2nd reprint, Pharmamed press, Hyderabad, p. 85,88-101,413-423. Joseph Busfield . cGMP, instrument and calibration. “Facilities, utilities and requirements, GXP, Ivt network”. Feb 21,2007;5-7. Available from: https://www.ivtnetwork.com/article/cgmp-equipment-instruments-and-calibration Guidelines : ICH. “ICH harmonization for better health”. Available from: https://www.ich.org/page/ich-guidelines Essential medicines and health products information portal. “WHO expert committee on specifications for pharmaceutical preparations”. World Health Organization. Technical report series no. 902-36th report.2002. 1/19/2022 Mehak Aggarwal 31

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