Process validation and its types

Introduction, Regulatory requirements for validation, Role of FDA, Code of Federal regulation, Validation life cycle, Significance of validation, Types of validation, Process valiadation, Phases of process validation, Process capability design, Process Qualification, Validation maintainance phase
Types of Process validation, Examples

1. PROCESS VALIDATION SUBMITTED BY ANJALI JOSHI M.PHARM 1

2. CONTENTS Introduction Regulatory requirements for Validation Validation Life Cycle Significance of Validation Types of Validation Process Validation Phases of Process Validation Types of Process Validation Example 2

3. INTRODUCTION DEFINITION OF VALIDATION:- Validation is establishing documented evidence which provides a high degree of assurance that a specific process, procedure or activity carried out in testing and then production maintains desired level of compliance at all stages. Validation is a key process for effective Quality Assurance its simple meaning is “ACTION OF PROVING” 3

4. CONT.... QA is the heart and soul of Quality control. QA = QC+ GMP Quality control is incomplete without production. Validation generally involves controlling of the critical step of a system which results in output of repeatable attributes. 4

5. Regulatory requirements for Validation ROLE OF FDA It is federal science based law enforcement agency mandated to protect public health. Validation process regulated by guideline and restriction set forth by FDA. The actual validation protocol, document & execution is responsibility of manufacturer but more specially this is responsibility of engineer. 5

6. CONT.... 2-CFR ( CODE OF FEDERAL REGULATION) This is body of regulation created by government, that set forth the guidelines pertaining to food and drug. The validation are embodied with in the scope of existing cGMP . The specific term PROCEED THE VALIDATION comes under the section 21CFR 211-100. 6

7. CONT.... 21CFR 211-110 :- Control procedure shall be established to monitor the output & to validate the performance of the manufacturing process that may be responsible for causing variability in the characteristics of in process material and drug material. 7

8. CONT.... 21 CFR 211. 100 There should be a written procedure for production and process control designed to assure that the drug products have the identify, strength, quality and purity they purport or are represented to posses. 8

9. CONT.... 21 CFR.113 Appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any validation of any sterilization process 9

10. Cont.... Validation under the document of cGMP broadly covers overall process of mfg. most of which are essentially facilities, equipment, component, procedure, and process qualification. Following sections of cGMP under 21 CFR 211 refer to the Validation:- 10

11. SECTIONS OF cGMP DETAILS 211. 68 Validation of computerized or automated process 211.84 (d) (2) Validation of suppliers test results for components when these test results are accepted in lieu of in house testing after receipt 211. 84 (d) (3) Validation of suppliers test results for containers & closures when these tests result are accepted in lieu of in house testing after receipt. 221. 110 (a) Validation of mfg. Processes to ensure batch uniformity & integrity of drug products. 211.113 (b) Validation of sterilization processes. 211.165 (e) Validation of analytical methodologies. ( explicitly defines validation) 211.194 (a) (2) Validation of analytical methodologies. ( implicitly defines validation) 11

12. CFR PART COVERS 21 CFR Part 210 Concerns current good manufacturing process in mfg. , processing, packaging of drug 21 CFR Part 211 Concerns cGMP for finished pharmaceuticals. 21 CFR Part 600 Concerns to production of biological derived product. 21 CFR Part 610 Safe distribution of biological derived product. 12

13. VALIDATION LIFE CYCLE 13

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15. SIGNIFICANCE of validation It reduces the risk of regulatory non compliance. Reduce the chances of product recall from the market. It may reduce the time to market the new drug product. Reduce the defect cost. Make the process better understood and assuring smooth running of process 15

16. CONT.... Validation therefore should be considered in following situation:- a) Totally new process b) New equipment c) Process & equipment which have been altered to suit changing priorities d) Process where the drug product test is poor & unreliable indicator of product quality 16

17. Types of validation 1. Analytical method validation. 2. Raw material validation. 3. Cleaning validation. 4. Calibration 5. Process validation a) Retrospective validation b) Concurrent validation c) Prospective validation d) Revalidation 17

18. CONT.... 6. Equipment validation a) Design Qualification b) Installation Qualification c) Operational Qualification d) Performance Qualification 18

19. PROCESS VALIDATION It is defined as a documented programme which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specification and quality characteristics. Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. 19

20. Cont...... This principle incorporates the understanding that the following conditions exist: Quality, safety, and efficacy are designed or built into the product. Quality cannot be adequately assured merely by in-process and finished-product inspection or testing. 20

21. PHASES OF PROCESS VALIDATION 1- Process capability design/ Process development 2- Process qualification a) Design of facility b) Qualification of utilities and equipment c) Process performance qualification d) PPQ protocol e) Process execution & report 3- Validation maintenance phase 21

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23. 1. PROCESS DEVELOPMENT Process development activities begin after the formulation has been developed. The process development program meet the following objectives:- 1. Develop a suitable process to produce a product which meets all a) Product specification b) Current good manufacturing process 2. Identify the crucial parameters that will affect the final product. 23

24. cont.... FDA in its Process Validation guideline states that a manufacturer should evaluate all factors that affect product quality when designing and undertaking a process validation study. Not all the parameters are crucial in order to define the final product characteristics so it is important to identify critical parameters 24

25. CONT.... Process development is mainly done to determine:- The no. and relative importance of critical parameters that influence process output. The numerical value and range for each of the critical parameters that result in acceptable process output. If the process capability is properly defined the process should result into output of consistence attributes when operated within defined limits of critical process parameters. 25

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28. 2-PROCESS QUALIFICATION PHASE It is generally designed to verify that all established limits of the critical process parameters are valid & satisfactory product can be produced even under the worst condition. It represents the actual study to show:- That all system, sub-systems of a mfg. process perform as intended. That all critical parameters operate within their assigned control limits. Such studies & trials which form the basis of process capability design and testing are verifiable and certifiable through proper documentation. 28

29. 3- VALIDATION MAINTAINENCE PHASE It requires frequent review of all process related requirements/ documents including validation audit report to assure that there have been no changes, deviation, failures, modification to the production process & that all SOP’S have been followed including change control procedures. At this stage the validation team also assured that there have been no change/ deviation that should have results in requalification and revalidation. 29

30. Types of process validation Generally there are four basic type of process validation:- a) Prospective validation b) Concurrent validation c) Retrospective validation d) Revalidation 30

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32. 1- PROSPECTIVE VALIDATION Prospective validation means validation done during the product development stage. When we develop a new manufacturing process each step in new process is required to be established that it will give us desired result. During this step the input resources are selected and clearly specified. 32

33. Cont.... E.g. - Material specification is clearly defined. - Equipment & process parameter are defined. -Operating condition if any specified. -Level of training of people can also be defined Infact , validation by this approach often leads to transfer of the manufacturing process from the development function to production. 33

34. 2- CONCURRENT VALIDATION Concurrent validation is validation which is carried out during production. Concurrent validation is appropriate when:- - It is more appropriate to validate process during routine production due to well understanding of process. - Extensive testing & monitoring ensure the desired quality characteristics of product with high degree of confidence 34

35. CONT... After three initial commercial batches are taken and process is handled over to mfg. personnel verification of process parameter still goes on. The process parameter is evaluated for mfg. facilities batch after batch & studied if any change or deviation is observed or required. 35

36. 3-RETROSPECTIVE VALIDATION It is used for facilities, processes and process control parameters used in operation that have not undergone in documented validation process. Validation of these facilities, processes and process control parameters is possible using historical data (QA/QC records) to provide the necessary documented evidence that the process is doing what is believed to do. Therefore this type of validation is only acceptable for well established processes. 36

37. 4- REVALIDATION Revalidation is the repetition of the validation process & it is required under following circumstances:- Change of formula, equipments, procedures or quality of raw material or even in physical variation of raw material i.e. Particle size. Major changes in critical process parameters. Changes in facilities & installation which influence process. On appearance of difference in result. 37

38. TABLET MANUFACTURING CRITICAL PARAMETER 38

39. example VALIDATION OF WET GRANULATION PROCESS Parameters to be considered during development & validation are- BINDER CONCENTRATION & ADDITION The optimal binder conc. will be need to be determined for the formulation. If the binder solution is sprayed, it is needed to be diluted enough so that it can be pumped through the nozzle. It should also be sufficiently concentrated to form granules without over wetting the materials. 39

40. Cont.... AMOUNT OF BINDER SOLUTION- Too much binder or solvent solution will over wet the materials and prolong the drying time. BINDER SOLUTION ADDITION RATE- Define the rate at which the binder solution can be added to the material. 40

41. CONT.... MIXING RATE It is the rate required to ensure the proper formation of granules. Over mixing of the granules can lead to harder granules and a lower dissolution rate. 41

42. REFERENCES Jain N.K. “Pharmaceutical Product Development” , CBS Publishers & Distributors, 2008. Page no. 524-549. Nash R.A. “Pharmaceutical Process Validation” 3 edition, Marcel & Dekker publication, Page no. 20-47. Guidance for Pharmaceutical Industry on Process Validation, USFDA, January 2011. 42

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