Validation (intro, scope, merits, ich, who guidelines)

intro, scope, merits, ich, who guidelines

1. VALIDATION ( Introduction, Scope,Merits,ICH, WHO Guidelines ) Presented By: Ms. Prajakta Sawant First Year M.Pharm (Roll No. 5) (Dept. of Pharmaceutics) Sub: Modern Pharmaceutics Alard College Of Pharmacy, Pune. Under the Guidance of: Dr. Nalanda Borkar Head of Department (Dept. of Pharmaceutics) Sub: Modern Pharmaceutics Alard College Of Pha rmacy, Pune. Monday, March 08, 2021 1

2. Contents : Introduction Need of Validation Planning for Validation Documentation of Validation Validation Master Plan Scope of Validation V Model for Validation Merits of Validation Types of Validation ⇨ Process Validation ⇨ Cleaning Validation ⇨ Equipment Validation ⇨ Validation of Analytical method Conclusion for Validation ICH Guidelines WHO Guidelines References  Monday, March 08, 2021 2

3. Introduction The concept of validation was first proposed by Food and Drug Administration ( FDA) officials, Ted Byers and Bud Loftus, in the mid 1970s in order to improve the quality of pharmaceuticals. Validation is "Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes." This is to maintain and assure a higher degree of quality of food and drug products. Monday, March 08, 2021 3

4. Need for validation Customer satisfaction Customer mandated Product liability Control production cost The development of the next generation Safety Monday, March 08, 2021 4

5. Planning for validation Validation activities can be organized by preparing the validation master plan (VMP). It should be brief, concise and clear. The EEC guide recommends the following contents in a VMP. Validation Policy Organizational structure of validation activities. Summary of facilities, systems, equipment and processes to be validated. Documentation format Planning and scheduling Change control reference to exiting documents. Monday, March 08, 2021 5

6. Documentation of Validation The validation activity cannot be completed without proper documentation of each and every minute activity with utmost details. Documentation of validation is generally of different types such as: Validation Master Plan(VMP) Validation Protocol(VP) Validation Reports(VR) Standard Operating Procedure(SOP) Monday, March 08, 2021 6

7. Validation master plan (V.M.P ) A Validation Master Plan is a document that summarizes the firm’s overall philosophy, intention and approaches to be used for establishing performance adequacy. A tool to track progress. Assignment of responsibility and team work. It identifies acceptance criteria before the start of validation. V.M.P gives idea about future performance:  What activities are to be performed?  Who is going to perform these activities?  When the activities should start and when they should get over?  What documents will be generated?  What the policy on revalidation? Monday, March 08, 2021 7

8. V.M.P. includes:  Premises  Processes  Products  Format for protocol and other documentation  List of relevant SOPs  Planning and scheduling  Location  Estimation of staffing requirements  A time plan of the project Monday, March 08, 2021 8

9. Guidelines on Preparing V.M.P.  V.M.P. write on A4 size paper.  File in a presentable form.  Have sufficient explanatory drawings.  Clearly divide the V.M.P. in different form.  It must be dated and signed properly by authorized persons.  If found any step inappropriate, discuss this with the F.D.A. people in advance. Relationship between validation and qualification : Qualification and validation are essentially the same. The term qualification is normally used for equipment and utilities, and validation is for systems and processes. In this sense, qualification can be seen as a part of validation. Monday, March 08, 2021 9

10. Scope of validation: Selection of raw material i.e. raw materials of desired quality attributes. Product design based on the expected performance. Process design to build the desired quality attributes in the product. Design of control parameters, such as change control, acceptance criteria, tolerance limits, etc. In process quality control parameters and sampling plans Finished product testing or evaluation criteria. Validation of related analytical process. Validation of related system, facility and equipment. Personnel training. Validation involves careful determination of criteria variable of the process, such as moisture content of granules, drying temperature of time, etc. and then establishment of acceptable range and tolerance limit for the same. A careful and continuous control of these variables will ensure consistent product quality. Monday, March 08, 2021 10

11. V model for validation: Monday, March 08, 2021 11

12. URS, FAT and SAT : User Requirement Specifications- Manufacturers should prepare a document that describes, for example, the utility or equipment to be sourced. The requirements and specifications for the utility or equipment should be defined by the user and should be documented in the URS. Factory Acceptance Test and Site Acceptance Test- Where appropriate, FAT and SAT should be performed to verify the suitability of the system at site, prior to the subsequent stages of qualification. This should be appropriately documented. Monday, March 08, 2021 12

13. Merits of validation : Assurance of quality compliance. Optimization of resources and manufacture product at lowest possible cost. Fewer failures, fewer rejects, fewer retests, fewer reworks, fewer wastage. It is a practice that must be followed for manufacturing, distribution, selling or license. Efficient production operation. Monday, March 08, 2021 13

14. Types of Validation The major types of Validation : Process validation Cleaning validation Equipment validation Validation of analytical methods  Monday, March 08, 2021 14

15. Process validation As per FDA, the Process Validation is defined as : " The collection of data from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. " Monday, March 08, 2021 15

16. Process validation life cycle/flow chart: Stage 1 - Process design Stage 2 - Process qualification Stage 3 - Continued process verification Monday, March 08, 2021 16

17. Types of Process validation:  Prospective validation.  Retrospective validation.  Concurrent validation.  Revalidation.  Monday, March 08, 2021 17

18. 1. Prospective validation Establishing documented evidences during development stage of process based on a predefined protocol. It is done prior to distribution of a new product or whenever there is a major change in the product characteristics. It is c ompulsory for sterile products. The activity continues till the first 3 batches are manufactured at full scale. Monday, March 08, 2021 18

19. Steps in prospective validation : 1. Formation of validation team 2. Preparation of validation master plan and validation protocol 3. Formulation development (preformulation studies and optimization) 4. Process development (process design, control & challenges in critical parameters etc.) 5. Facility development (building, support systems, staff) 6. Process qualification (checked for worst case conditions o ensure reproducibility) 7. Product qualification 8. Change control Monday, March 08, 2021 19

20. 2. Concurrent Process validation Carried out during normal production. It is useful only if process is well understood during development stage. The nature and specifications of subsequent in- process and final tests are based on the evaluation of the results of such monitoring. 3. Retrospective process validation (based on analysis of historical data) Carried out on the basis of database generated during previous production of the product. Recorded difficulties, variation and failures in production are analysed to determine the limits of process parameters. Thus, it is useful in establishing priorities for validation. Monday, March 08, 2021 20

21. 4. Revalidation It is needed to ensure that the changes in process or in process environment do not adversely affect the process characteristic and product quality. Revalidation is required when:- a) There is a major change in facility, equipment, process, etc. b) Periodic revalidation is scheduled at regular interval to control and identify a gradual change in the process. Monday, March 08, 2021 21

22. Cleaning validation Definition: “A process of attaining and documenting sufficient evidence to give reasonable assurance, given the current state of Science and Technology, that the cleaning process under consideration does, and / or will do, what it purpose is to do.” Objective:  To minimize cross contamination.  To determine efficiency of cleaning process.  To do troubleshooting in case if problem is identified in the cleaning process and give suggestions to improve the process.  Monday, March 08, 2021 22

23. Source of contamination:  Cross contamination of one product into another.  Product contamination by a foreign material.  Microbial contamination. Cleaning methods:  Manual cleaning method.  Semi automated procedures.  Fully automated procedures. Monday, March 08, 2021 23

24. Factors Influencing Cleaning validation :  Product.  Equipment.  Facilities.  Cleaning methods.  Cleaning agents.  Sampling.  Testing, Limits, and acceptance criteria. Monday, March 08, 2021 24

25. Cleaning validation flow chart: Monday, March 08, 2021 25

26. Equipment Validation Definition : As per FDA , "Action of proving that any equipment works correctly and leads to the expected result is equipment validation . It is not a single step activity but instead result from many discrete activities. " Steps involved:  User requirement specification  Design qualification  Installation qualifications  Operational qualifications  Performance qualification Monday, March 08, 2021 26

27. Equipment Validation Flow Chart: Monday, March 08, 2021 27

28. Validation of analytical methods Definition : “The process by, which it is established, by laboratory studies, that the performance characteristics of the method meet the requirements for the intended analytical application”. Accuracy : The closeness of test results obtained by that method to the true value. This accuracy should be established across its range. Precision: The degree of agreement among individual test results when the method is applied repeatedly to multiple sampling of a homogenous sample. Monday, March 08, 2021 28

29. Specificity : The ability to assess unequivocally the analyte in the presence of components that may be expected to be present, such as impurities, degradation products and matrix components. Limit of Quantitation : A characteristic of quantitative assays for low levels of compounds in sample matrices such as impurities in bulk substances and degradation products in finished pharmaceuticals. It is the lowest amount of analyte in a sample that can be determined with acceptable precision and accuracy under the stated experimental conditions. Monday, March 08, 2021 29

30. Range : Interval between the upper and lower of analyte (including these levels) that have been demonstrated to be determined with a suitable level of precision , accuracy and linearity using the method as written. The range is normally expressed in the same units as test results obtained by the analytical method ( e.g. Percentage , parts per million, etc.). Ruggedness: The degree of reproducibility of test results obtained by the analysis of the same sample under a variety of conditions such as different laboratories, different analysts, different instruments, different lots of reagents, different elapsed assay times, different assay temperatures, different days, etc. Monday, March 08, 2021 30

31. Robustness: A measure of its capacity to remain unaffected by small but deliberate variations in method parameters and provides an indication of its reliability during normal usage. Linearity : Its ability to elicit tests that are directly or by a well defined mathematical transformations proportional to the concentration of analyte in samples within a given range. Limit of Detection : The lowest amount of analyte in a sample that can be detected but not necessarily quantitated, under the stated experimental conditions. Monday, March 08, 2021 31

32. Conclusion for validation: Validation has been proven assurance for the process efficiency and sturdiness and it is the full fledged quality attributing tool for the pharmaceutical industries. Validation is the commonest word in the areas of drug development, manufacturing and specification of finished products. It also renders reduction in the cost linked with process monitoring, sampling and testing. Apart from all the consistency and reliability of a validated process to produce a quality product, it is very important for an industry. Monday, March 08, 2021 32

33. ICH GUIDELINES INTRODUCTION The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration.  Monday, March 08, 2021 33

34. AIM : The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 as a joint regulatory/industry project to improve, through harmonization, the efficiency of the process for developing and registering new medicinal products in Europe, Japan and the United States, in order to make these products available to patients with a minimum of delay. The six parties to ICH represent the regulatory and research- based industry in the three regions, Europe, Japan and the USA, where the vast majority of new medicines are currently developed. Monday, March 08, 2021 34

35. ICH PARTIES European Commission - European Union (EU). European Federation of Pharmaceutical Industries and Associations (EFPIA). Ministry of Health, Labour and Welfare, Japan (MHLW). Japan Pharmaceutical Manufacturers Association (JPMA). US Food and Drug Administration (FDA). Pharmaceutical Research and Manufacturers of America (PhRMA).  Monday, March 08, 2021 35

36. OBECTIVES More economical use of human, animal, and material resources. Elimination of unnecessary delay in the global development & availability of new medicines. Maintaining safeguards on Quality, safety, efficacy and regulatory obligations to protect public health. Monday, March 08, 2021 36

37. TOPIC OF ICH Four Broad Categories - QSEM Quality (Q): those relating to chemical and pharmaceutical Quality Assurance (Stability Testing, Impurity Testing, etc.) Safety (S): those relating to in vitro and in vivo pre-clinical studies (Carcinogenicity Testing, Genotoxicity Testing, etc.) Efficacy (E): those relating to clinical studies in human subject (Dose Response Studies, Good Clinical Practices, etc.) Multidisciplinary (M): cross-cutting Topics which do not fit uniquely into one of the above categories (MedDRA, ESTRI, M3, CTD, M5) Monday, March 08, 2021 37

38. OVERVIEW OF ICH QUALITY:  Q1A(R2): STABILITY TESTING OF NEW DRUGS AND PRODUCTS  Q1B: PHOTOSTABILITY TESTING  Q1C : STABILITY TESTING OF NEW DOSAGE FORMS  Q1D: BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF DRUG SUBSTANCES AND DRUG PRODUCTS.  Q1E: EVALUATION OF STABILITY DATA  Q1F: STABILITY DATA PACKAGE FOR REGISTRATION IN CLIMATIC ZONES III AND IV  Q2A: DEFINTIONS AND TERMINOLOGY: ANALYTICAL VALIDATION  Q2B: METHODOLOGY  Q3A(R2) : IMPURITIES IN NEW DRUG SUBSTANCES  Q3B(R2) : IMPURITIES IN NEW DRUG PRODUCT  Q3C(R3) : IMPURITIES GUIDELINES FOR RESIDUAL SOLVENTS Monday, March 08, 2021 38

39.  Q4: PHARMACOPOEIA  Q4A: PHARMACOPOEIAL HARMONIZATION  Q5A: VIRAL SAFETY EVALUATION  Q5B: GENETIC STABILITY  Q5C: STABILITY OF BIOTECHNOLOGY PRODUCTS  Q5D: CELL SUBSTRATES 12  Q6A: SPECIFICATIONS, TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR NEW DRUG SUBSTANCES AND PRODUCTS  Q6B : SPECIFICATION TEST PROCEDURE AND ACCEPTANCE CRITRIA FOR BIOTECHNOLOGICAL/ BIOLOGICAL PRODUCTS  Q7A: GMP FOR ACTIVE PHARMACEUTICAL INGREDIENTS  Q8: PHARMACEUTICAL DEVELOPMENT  Q9: QUALITY RISK MANAGEMENT  Q10: PHARMACEUTICAL QUALITY SYSTEM  Monday, March 08, 2021 39

40. SAFETY :  S1A: GUIDELINE ON THE NEED FOR CARCINOGENICITY STUDIES OF PHARMACEUTICALS  S1B: TESTING FOR CARCINOGENICITY OF PHARMACEUTICALS  S1C(R2): DOSE SELECTION FOR CARCINOGENICITY STUDIES OF PHARMACEUTICALS  S2(R1): GUIDANCE ON GENOTOXICITY TESTING AND DATA INTERPRETATION FOR PHARMACEUTICALS INTENDED FOR HUMAN USE  S3A: NOTE FOR GUIDANCE ON TOXICOKINETICS: THE ASSESSMENT OF SYSTEMIC EXPOSURE IN TOXICITY STUDIES  S3B: PHARMACOKINETICS:GUIDANCE FOR REPEATED DOSE TISSUE DISTRIBUTION STUDIES  S4: DURATION OF CHRONIC TOXICITY TESTING IN ANIMALS (RODENT AND NON RODENT TOXICITY TESTING) Monday, March 08, 2021 40

41.  S5(R2): DETECTION OF TOXICITY TO REPRODUCTION FOR MEDICINAL PRODUCTS & TOXICITY TO MALE FERTILITY  S6(R1): ADDENDUM TO ICH S6: PRECLINICAL SAFETY EVALUATION OF BIOTECHNOLOGY-DERIVED PHARMACEUTICALS  S6: PRECLINICAL SAFETY EVALUATION OF BIOTECHNOLOGY- DERIVED PHARMACEUTICALS  S7A: SAFETY PHARMACOLOGY STUDIES FOR HUMAN PHARMACEUTICALS  S7B: THE NON-CLINICAL EVALUATION OF THE POTENTIAL FOR DELAYED VENTRICULAR REPOLARIZATION (QT INTERVAL PROLONGATION) BY HUMAN PHARMACEUTICALS  S8: IMMUNOTOXICITY STUDIES FOR HUMAN PHARMACEUTICALS  S9: NONCLINICAL EVALUATION FOR ANTICANCER PHARMACEUTICALS Monday, March 08, 2021 41

42. 3) EFFICACY :  E1: THE EXTENT OF POPULATION EXPOSURE TO ASSESS CLINICAL SAFETY  E2A: CLINICAL SAFETY DATA MANAGEMENT  E2B(R2): MAINTENANCE OF THE ICH GUIDELINE ON CLINICAL SAFETY DATA MANAGEMENT  E2B(R3): REVISION OF THE ICH GUIDELINE ON CLINICAL SAFETY DATA MANAGEMENT  DATA ELEMENTS FOR TRANSMISSION OF INDIVIDUAL CASE SAFETY REPORTS  E2C(R1): CLINICAL SAFETY DATA MANAGEMENT: PERIODIC SAFETY UPDATE REPORTS FOR MARKETED DRUGS  E2D: POST-APPROVAL SAFETY DATA MANAGEMENT: DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING Monday, March 08, 2021 42

43.  E2E: PHARMACOVIGILANCE PLANNING  E2F: DEVELOPMENT SAFETY UPDATE REPORT  E3: STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS  E4: DOSE-RESPONSE INFORMATION TO SUPPORT DRUG REGISTRATION  E5(R1): ETHNIC FACTORS IN THE ACCEPTABILITY OF FOREIGN CLINICAL DATA  E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE  E7: STUDIES IN SUPPORT OF SPECIAL POPULATIONS:GERIATRICS 19  E8: GENERAL CONSIDERATIONS FOR CLINICAL TRIALS Monday, March 08, 2021 43

44.  E9: STATISTICAL PRINCIPLES FOR CLINICAL TRIALS  E10: CHOICE OF CONTROL GROUP AND RELATED ISSUES IN CLINICAL TRIALS  E11: CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS IN THE PEDIATRIC POPULATION  E12: PRINCIPLES FOR CLINICAL EVALUATION OF NEW ANTIHYPERTENSIVE DRUGS  E14: THE CLINICAL EVALUATION OF QT/QTC INTERVAL PROLONGATION AND PROARRHYTHMIC POTENTIAL FOR NON-ANTIARRHYTHMIC DRUGS  E15: DEFINITIONS FOR GENOMIC BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC DATA AND SAMPLE CODING CATEGORIES  E16: GENOMIC BIOMARKERS RELATED TO DRUG RESPONSE Monday, March 08, 2021 44

45. MULTIDISCIPLINARY GUIDELINES :  M1- MedDRA : Medical Terminology  M2- ESTRI: Electronic Standards for the Transfer of Regulatory Information  M3- (R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals  M4- CTD: The Common Technical Document  M5 : Data Elements and Standards for Drug Dictionaries  Monday, March 08, 2021 45

46. WHO (World Health Organization) GUIDELINES These guidelines focus mainly on the overall concept of validation and are not intended to be prescriptive in specific validation requirements. This document serves as general guidance only and the principles may be considered useful in its application in the manufacture and control of starting materials and finished pharmaceutical products (FPPs), as well as other areas. Validation of specific processes and systems, for example, in sterile product manufacture, requires much more consideration and a detailed approach that is beyond the scope of this document. Monday, March 08, 2021 46

47. Glossary The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts. Calibration The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (for example, weight, temperature and pH), recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established. Computer Validation Documented evidence which provides a high degree of assurance that a computerized system analyses, controls and records data correctly and that data processing complies with predetermined specifications. Commissioning The setting up, adjustment and testing of equipment or a system to ensure that it meets all the requirements, as specified in the user requirement specification, and capacities as specified by the designer or developer. Commissioning is carried out before qualification and validation. Monday, March 08, 2021 47

48. Concurrent Validation Cleaning Validation Design Qualification (DQ) Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ) Process Validation Prospective Validation Retrospective Validation Revalidation Validation Validation Master Plan (VMP) Monday, March 08, 2021 48

49. Good Engineering Practices (GEP) : Established engineering methods and standards that are applied throughout the project life-cycle to deliver appropriate, cost-effective solutions. Qualification: Action of proving and documenting that any premises, systems and equipment are properly installed, and/or work correctly and lead to the expected results. Qualification is often a part (the initial stage) of validation, but the individual qualification steps alone do not constitute process validation. Standard operating procedure (SOP) : An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master batch production documentation. Monday, March 08, 2021 49

50. Validation Protocol (or plan) (VP) : A document describing the activities to be performed in a validation, including the acceptance criteria for the approval of a manufacturing process or a part thereof for routine use. Validation Report (VR) : A document in which the records, results and evaluation of a completed validation programme are assembled and summarized. It may also contain proposals for the improvement of processes and/or equipment. Verification : The application of methods, procedures, tests and other evaluations, in addition to monitoring, to determine compliance with the GMP principles. Worst Case : A condition or set of conditions encompassing the upper and lower processing limits for operating parameters and circumstances, within SOPs, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily include product or process failure. Monday, March 08, 2021 50

51. Periodic revalidation: Periodic revalidation should be performed to assess process changes that may occur gradually over a period of time, or because of wear of equipment . The following should be considered when periodic revalidation is performed: master formulae and specifications; SOPs; records (e.g. of calibration, maintenance and cleaning); and analytical methods . Revalidation after change: Revalidation should be performed following a change that could have an effect on the process, procedure, quality of the product and/or the product characteristics. Revalidation should be considered as part of the change control procedure. The extent of revalidation will depend on the nature and significance of the change(s). Changes should not adversely affect product quality or process characteristics. Changes requiring revalidation should be defined in the validation plan. Monday, March 08, 2021 51

52. CHANGE CONTROL: Changes should be controlled in accordance with a SOP as changes may have an impact on a qualified utility, system or piece of equipment, and a validated process and/or procedure. The procedure should describe the actions to be taken, including the need for and extent of qualification or validation to be done. Changes should be formally requested, documented and approved before implementation. Records should be maintained. PERSONNEL: Personnel should demonstrate that they are appropriately qualified, where relevant. Personnel requiring qualification include, for example: — laboratory analysts; — personnel following critical procedures; — personnel doing data entry in computerized systems; and — risk assessors. Monday, March 08, 2021 52

53. References: https://www.slideshare.net/ManikantPrasadShah/validation-scope-of-validation-urs-who-guidelines-for-validation Assessed Date: 08/03/2021 https://www.slideshare.net/shettyuc/new-who-guidance-on-process-validation Assessed Date: 08/03/2021 https://www.slideshare.net/Anshul2593/ich-guidelines-72292250 https://www.slideshare.net/rks19761/pharmaceutical-process-validation?next_slideshow=1 Assessed Date: 08/03/2021 https://www.slideshare.net/dalvirahul16/pharmaceutical-validation-ppt Assessed Date: 08/03/2021 https://www.slideshare.net/sagarsavale1/cleaning-validation-62056468 Assessed Date: 08/03/2021 https://www.who.int/medicines/areas/quality_safety/quality_assurance/SupplementaryGMPValidationTRS937Annex4.pdf?ua=1 Assessed Date: 08/03/2021 https://www.slideshare.net/ssuserfe3019/ich-who-guidelines-on-validation Assessed Date: 08/03/2021 Monday, March 08, 2021 53